Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH:6][C:5]=1[O:14]C.Cl.[NH+]1C=CC=C[CH:19]=1>>[CH2:1]([O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH:6][C:5]=1[OH:14])[CH3:19]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)cc1OC
Reactant: c1cc[nH+]cc1
Agent: Cl
Product: CCOC(=O)c1ccc(S(C)(=O)=O)cc1O
Temperature: 180 °C
Yield: 56.7 %

Procedure:
A mixture of 10 (15 g) and pyridinium hydrochloride (45 g) was heated under an inert atmosphere at 180° C. for 1.5 h and cooled. The mixture was partitioned between EtOAc and aqueous HCl (5%). The organic layer was washed with aqueous HCl (5%), dried, filtered, and concentrated. A solution of the resulting residue in EtOH (400 mL) was treated with concentrated H2SO4 (10 mL) and heated overnight at 75° C. After cooling, the mixture was concentrated and partitioned between EtOAc and saturated aqueous NaHCO3. The organic layer was extracted with 1 M NaOH (4 times). This combined aqueous layer was brought to acidic pH by addition of aqueous HCl (5%) and was extracted with EtOAc. This organic layer was dried (MgSO4), filtered, and evaporated giving 8.5 g of 2-hydroxy-4-methanesulfonyl-benzoic acid ethyl ester 11 as a solid.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:14][CH3:15])[CH:5]=1)=O.P(Cl)(Cl)(Cl)(Cl)Cl.[NH2-].[Na+].N>C1COCC1.CCOCC.O>[C:2]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:14][CH3:15])[CH:5]=1)#[CH:1]
Reactant: COc1cccc2cc(C(C)=O)ccc12
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: N
Agent: [NH2-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: C#Cc1ccc2c(OC)cccc2c1
Temperature: 0 °C
Reaction time: 72 h

Procedure:
Methyl (5-methoxynaphth-2-yl)ketone (0.25 moles) and phosphorus pentachloride (0.31 moles) are placed in a 3-neck flask equipped with a mechanical stirrer, a condenser connected to a nitrogen inlet, and a thermometer. The mixture is stirred at 33°-35° C for 3 days. The cooled reaction mixture is poured onto 800 g of ice and extracted with 3 × 500 ml of ether. The ether fraction is washed with 2 × 100 ml water 4 × 100 ml of 5% sodium hydroxide, 3 × 50 ml water, 2 × 50 ml of saturated saline and dried over sodium sulfate. The ether is removed to give the chlorinated intermediate. The intermediate is dissolved in anhydrous THF (200 ml) and is added dropwise to a freshly prepared solution of sodamide in liquid ammonia, using a dry-ice condenser. The reaction mixture is allowed to stir at room temperature overnight; then, it is poured into 50 ml of water and 500 ml of ether. The ether fraction is washed with 3 × 50 ml water and solvent gives a residue which is distilled to give 2-ethynyl-5-methoxynaphthalene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][Li])=[CH:5][CH:4]=1.[CH2:12]([Sn:16](Cl)([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH3:15].[Cl-].[NH4+]>CCCCCC.C1COCC1.C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][Sn:16]([CH2:17][CH2:18][CH2:19][CH3:20])([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:12][CH2:13][CH2:14][CH3:15])=[CH:5][CH:4]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: [Li]CSc1ccc(OC)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)CSc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Using the apparatus and procedure of Example I, 100 ml. of an approximately one-molar solution of (p-methoxyphenylthio)methyllithium in hexane-THF solvent is added dropwise with stirring to 0.1 mole of tributyltin chloride dissolved in THF. The temperature is maintained by means of an ice bath in the range of from 0° C to 10° C. Following the complete addition over a one-quarter hour period, the reaction mixture is stirred for two hours at room temperature and hydrolyzed by pouring into aqueous one-molar ammonium chloride. Extraction from the hydrolyzate with ether solvent and purification by vacuum distillation yields the desired product, (p-methoxyphenylthiomethyl)tributyltin.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1/[CH:7]=[CH:8]/[C:9]1[C:17]2[C:12](=[CH:13][C:14]([CH:18]=[O:19])=[CH:15][CH:16]=2)[N:11](COCC[Si](C)(C)C)[N:10]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1/[CH:7]=[CH:8]/[C:9]1[C:17]2[C:12](=[CH:13][C:14]([CH:18]=[O:19])=[CH:15][CH:16]=2)[NH:11][N:10]=1
Reactant: Cc1ncsc1/C=C/c1nn(COCC[Si](C)(C)C)c2cc(C=O)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1ncsc1/C=C/c1n[nH]c2cc(C=O)ccc12
Yield: 74.3 %

Procedure:
A mixture of (E)-3-(2-(4-methylthiazol-5-yl)vinyl)-1-((2-(trimethylsilyl)ethoxy)-methyl)-1H-indazole-6-carbaldehyde (30 mg, 0.075 mmol) and tetrabutyl-ammonium fluoride (1.0 M in THF, 0.37 mL, 0.37 mmol) in anh. THF (10 mL) was refluxed under Ar for 1 d. The reaction mixture was then concentrated under reduced pressure and purified by prepTLC (SiO2 10% MeOH/DCM) to provide the title compound (15 mg, 74%) as a tan solid (7.0 mg, 21%). MS ESI 270.0 [M+H]+, calcd for [C14H11N3OS+H]+ 270.3.
Reaction SMILES: C(OCC)(=O)C.Cl.C(O[C:13]([N:15]([N:17]1[C:26]2[C:21](=[CH:22][C:23]([F:29])=[C:24]([F:28])[C:25]=2[F:27])[C:20](=[O:30])[C:19]([C:31]([O:33][CH3:34])=[O:32])=[CH:18]1)C)=O)(C)(C)C.C(=O)([O-])O.[Na+]>O.C(Cl)Cl>[F:29][C:23]1[CH:22]=[C:21]2[C:26](=[C:25]([F:27])[C:24]=1[F:28])[N:17]([NH:15][CH3:13])[CH:18]=[C:19]([C:31]([O:33][CH3:34])=[O:32])[C:20]2=[O:30]
Reactant: COC(=O)c1cn(N(C)C(=O)OC(C)(C)C)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: CNn1cc(C(=O)OC)c(=O)c2cc(F)c(F)c(F)c21
Reaction time: 1 h
Yield: 50.4 %

Procedure:
To ethyl acetate solution (55 ml) of 4N hydrochloric acid, was added methyl 1-(N-tert-butoxycarbonyl-N-methylamino)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (10.85 g) with ice-cooling, and the mixture was stirred for one hour at the same temperature and then for 14 hours at room temperature. The mixture was concentrated under reduced pressure to obtain a solid. The solid was poured into a mixture comprising methylene chloride (150 ml) and water (150 ml). The suspension was neutralized with sodium hydrogencarbonate. The precipitates were taken out by filtration, washed with water and dried with phosphorus pentaoxide to obtain a solid. The solid was recrystallized from a liquid mixture of methylene chloride and diisopropyl ether to obtain methyl 6,7,8-trifluoro-1-methylamino-1,4-dihydro-4-oxoquinoline-3-carboxylate (4.05 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:13]=[CH:12][S:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I:14]N1C(=O)CCC1=O.CCCCCC.CCOC(C)=O>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1[I:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)(C)OC(=O)Nc1ccsc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)Nc1ccsc1I
Reaction time: 0.33 h
Yield: 92.3 %

Procedure:
In a manner analogous to Campaigne, E. and Monroe, P. A. J.A.C.S., 76, 2447-2450 (1954), to a boiling solution of (tert-butoxy)-N-(3-thienyl)carboxamide (21.0 g, 0.1 mol, preparation 5) in methylene chloride (400 mL) is added N-iodosuccinimide (23.7 g, 0.1 mol) in small portions. The heating bath is then set to 65° C. for 20 min. TLC (Hexane/AcOEt 9:1) shows complete consumption of starting material. The reaction is taken to room temperature, the solvent is evaporated and the crude is purified by flash chromatography (Silica gel-Hexane/EtOAc 9:1) to obtain 30.0 g (88%) of title compound as a white solid.
Reaction SMILES: [CH2:1]([N:8]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH:9]1[CH2:13][CH:12]([C:14](=O)[CH2:15][NH:16][C:17]2[N:18]=[C:19]3[CH:25]=[CH:24][N:23]([S:26]([C:29]4[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=4)(=[O:28])=[O:27])[C:20]3=[N:21][CH:22]=2)[CH:11]([CH3:37])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1>>[CH2:1]([N:8]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH:9]1[CH2:13][CH:12]([C:14]2[N:18]3[C:19]4[CH:25]=[CH:24][N:23]([S:26]([C:29]5[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=5)(=[O:28])=[O:27])[C:20]=4[N:21]=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:11]([CH3:37])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NCC(=O)C4CC(N(Cc5ccccc5)Cc5ccccc5)CC4C)cnc32)cc1
Agent: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2ncc(C4CC(N(Cc5ccccc5)Cc5ccccc5)CC4C)n23)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
A mixture of 1-(4-(dibenzylamino)-2-methylcyclopentyl)-2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)ethanone (5.32 g, 8.75 mmol) and Lawesson's reagent (1.88 g, 4.64 mmol) was heated at about 60° C. for about 2 h. Lawesson's reagent (1.88 g, 4.64 mmol) was added. The reaction mixture was stirred at about 60° C. for about 1 h. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography eluting with a gradient of 0-8% MeOH in DCM to yield N,N-dibenzyl-3-methyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentanamine (4.47 g, 87%) as a brown amorphous solid: LC/MS (Table 1, Method a) Rt=2.99 min; MS m/z 590 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([NH:6][C:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[C:13]([O:15]CC)=O)[CH:3]=[N:2]1>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[O:15]=[C:13]1[C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C:7]=2[NH:6][C:4]2[CH:5]=[N:1][NH:2][C:3]1=2
Reactant: CCOC(=O)C1=C(Nc2cn[nH]c2)CCCC1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=c1c2c([nH]c3cn[nH]c13)CCCC2
Temperature: 25 °C
Yield: 91.9 %

Procedure:
Ethyl 2-(pyrazol-4-ylamino)cyclohexene-1-carboxylate (8.5 g, 0.036 mole) was added rapidly to refluxing Dowtherm A (250 ml) under nitrogen and the mixture heated under reflux for a further 15 minutes, before allowing to cool to room temperature. The mixture was diluted with 60°-80° petroleum ether (200 ml) and the solid then filtered off, washed well with petroleum ether and then ethanol, before drying under vacuum to give the title compound as a white solid (6.26 g, 92%), m.p. >325° C. Found: C, 63.20; H, 5.85; N, 22.20% C10H11N3O requires C, 63.50; H, 5.85; N, 22.20%
Reaction SMILES: [F:1][C:2]([F:11])([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)[CH:3]=O.[CH3:12][C:13]([CH3:27])([CH3:26])[CH2:14][C@H:15]([NH2:25])[C:16]12[O:23][CH2:22][C:19]([CH3:24])([CH2:20][O:21]1)[CH2:18][O:17]2>>[F:1][C:2]([F:11])([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)[CH:3]=[N:25][C@H:15]([C:16]12[O:17][CH2:18][C:19]([CH3:24])([CH2:20][O:21]1)[CH2:22][O:23]2)[CH2:14][C:13]([CH3:27])([CH3:12])[CH3:26]
Reactant: CC(C)(C)C[C@H](N)C12OCC(C)(CO1)CO2
Reactant: O=CC(F)(F)c1ccccn1
Product: CC(C)(C)C[C@H](N=CC(F)(F)c1ccccn1)C12OCC(C)(CO1)CO2

Procedure:
DIBAL-H (2 ml) was added to a solution of 2,2-difluoro-2-pyridin-2-ylacetic acid ethyl ester (400 mg, 2 mmol) in dry ether (2.5 ml) at −78° C. After 4 h, methanol (0.5 ml) and water (2 ml) were added. The reaction mixture was warmed to room temperature and the emulsion formed was filtered through celite and washed with ether. The organic layer was separated, washed with brine and dried over MgSO4. The solvent was evaporated to get a thick liquid. To the crude liquid was added DCM (1 ml) and hexane (3 ml) and left overnight in cold. The precipitated solid was filtered and washed with hexane to give 2,2-difluoro-2-pyridin-2-ylacetaldehyde (150 mg) as a white solid. 2,2-Difluoro-2-pyridin-2-ylacetaldehyde was reacted with 3,3-dimethyl-1(S)-(4-methyl-2,6,7-trioxabicyclo[2.2.2]oct-1-yl)butylamine as described in Example 1, Step 8 above to give (2,2-difluoro-2-pyridin-2-ylethylidene)-[3,3-dimethyl-1(S)-(4-methyl-2,6,7-trioxabicyclo[2.2.2]oct-1-yl)butyl]amine (600 mg) as a thick liquid.
Reaction SMILES: C1(N(CCO)C(C2C(OCC3C=CC=CC=3)=C(O)N=C(CC3(C4C=CC=CC=4)CCCC3)N=2)=O)CC1.[Si]([O:44][CH2:45][CH2:46][N:47]([CH:77]1[CH2:82][CH2:81][O:80][CH2:79][CH2:78]1)[C:48]([C:50]1[C:55]([O:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)=[C:54]([OH:64])[N:53]=[C:52]([CH2:65][C:66]2([C:71]3[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=3)[CH2:70][CH2:69][CH2:68][CH2:67]2)[N:51]=1)=[O:49])(C(C)(C)C)(C)C>>[OH:44][CH2:45][CH2:46][N:47]([CH:77]1[CH2:78][CH2:79][O:80][CH2:81][CH2:82]1)[C:48]([C:50]1[C:55]([O:56][CH2:57][C:58]2[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=2)=[C:54]([OH:64])[N:53]=[C:52]([CH2:65][C:66]2([C:71]3[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=3)[CH2:70][CH2:69][CH2:68][CH2:67]2)[N:51]=1)=[O:49]
Reactant: CC(C)(C)[Si](C)(C)OCCN(C(=O)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1)C1CCOCC1
Agent: O=C(c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1)N(CCO)C1CC1
Product: O=C(c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1)N(CCO)C1CCOCC1
Yield: 90.6 %

Procedure:
This compound was prepared following the same method as described for 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid cyclopropyl-(2-hydroxyethyl)-amide (285) from 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-(tetrahydro-pyran-4-yl)-amide (308) (540 mg, 0.83 mmol). The product was obtained as a white solid (400 mg, 89.99%).
Reaction SMILES: F[C:2]1[C:19]([F:20])=[C:18]2[C:5]([CH2:6][C:7]3([C@H:16]4[C@H:24]([CH3:25])[O:23][C@H:22]([CH3:26])[CH2:21][N:17]42)[C:12](=[O:13])[NH:11][C:10](=[O:14])[NH:9][C:8]3=[O:15])=[CH:4][C:3]=1/[C:27](=[N:29]/[OH:30])/[CH3:28]>CS(C)=O>[F:20][C:19]1[C:2]2[O:30][N:29]=[C:27]([CH3:28])[C:3]=2[CH:4]=[C:5]2[C:18]=1[N:17]1[CH2:21][C@@H:22]([CH3:26])[O:23][C@@H:24]([CH3:25])[C@@H:16]1[C:7]1([C:8](=[O:15])[NH:9][C:10](=[O:14])[NH:11][C:12]1=[O:13])[CH2:6]2
Reactant: C/C(=N\O)c1cc2c(c(F)c1F)N1C[C@@H](C)O[C@@H](C)[C@@H]1C1(C2)C(=O)NC(=O)NC1=O
Solvent: CS(C)=O
Product: Cc1noc2c(F)c3c(cc12)CC1(C(=O)NC(=O)NC1=O)[C@H]1[C@H](C)O[C@H](C)CN31
Temperature: 120 °C

Procedure:
To a solution of (2R,4S,4aS)-rel-9,10-difluoro-8-[(1E)-N-hydroxyethanimidoyl]-2,4-dimethyl-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione (Intermediate 16, 250 mg, 0.63 mmol) in DMSO, was added K—O-t-Bu (47 mg, 0.636 mmol) and the mixture was heated to 120° C. for 12 hours. After cooling to room temperature and removal of solvent, the residue was purified using normal phase HPLC (95:5: Hexane:IPA) to give the title compound as a racemic mixture in the form of a pale yellow solid. Yield: 50 mg (20%).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[Mg].C(Br)C.[NH2:9][C:10]1[N:14]([C:15]2[C:20]([Cl:21])=[CH:19][C:18]([C:22]([F:25])([F:24])[F:23])=[CH:17][C:16]=2[Cl:26])[N:13]=[C:12]([C:27]([F:30])([F:29])[F:28])[C:11]=1[S:31]C#N>C(OCC)C.O>[NH2:9][C:10]1[N:14]([C:15]2[C:20]([Cl:21])=[CH:19][C:18]([C:22]([F:23])([F:24])[F:25])=[CH:17][C:16]=2[Cl:26])[N:13]=[C:12]([C:27]([F:28])([F:30])[F:29])[C:11]=1[S:31][CH2:1][CH3:2]
Reactant: CC[Mg]Br
Reactant: N#CSc1c(C(F)(F)F)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Agent: [Mg]
Solvent: O
Solvent: CCOCC
Solvent: CCBr
Product: CCSc1c(C(F)(F)F)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of ethyl magnesium bromide, prepared from magnesium (0.57 g) and ethyl bromide (2.6 g) in dry diethyl ether (25 ml), was added dropwise to a stirred solution of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-thiocyanato-3-trifluoromethylpyrazole (5.0 g) in dry ether (50 ml) at -20° C. After stirring for a further 2 hours at room temperature, water (130 ml) was carefully added, and stirring maintained for 0.25 hour. The ether layer was separated, dried over anhydrous magnesium sulphate, and evaporated in vacuo to give a yellow gum. Purification by chromatography on silica (Merck, 230-400 mesh, 0.7 kg cm-2) eluting with dichloromethane-petroleum ether (1:1) gave a product, which recrystallized from hexane to furnish 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-ethylthio-3-trifluoromethylpyrazole, in the form of white needles, m.p. 116°-116.5° C.
Reaction SMILES: [CH:1]([N:4](C(C)C)CC)(C)[CH3:2].[Si:10]([O:17][CH:18]([CH2:22][S:23][S:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([OH:21])=[O:20])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].BrCC#N>CN(C=O)C.C(OCC)C>[Si:10]([O:17][CH:18]([CH2:22][S:23][S:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([O:21][CH2:2][C:1]#[N:4])=[O:20])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)SSCC(O[Si](C)(C)C(C)(C)C)C(=O)O
Agent: N#CCBr
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)SSCC(O[Si](C)(C)C(C)(C)C)C(=O)OCC#N
Reaction time: 1.5 h
Yield: 71 %

Procedure:
Diisopropylethylamine (98.0 μl, 0.56 mmol) was added to a solution of 2-(tert-butyldimethylsilyloxy)-3-(tert-butyldisulfanyl)propionic acid prepared by the method known in the literature (J. Am. Chem. Soc. 2008, 130, 4919) (Compounds 24, 60.0 mg, 0.185 mmol) and 2-bromoacetonitrile (26.0 μl, 0.373 mmol) in DMF (1.8 ml) at room temperature, and the reaction solution was stirred at the same temperature for 1.5 hours. The reaction mixture was diluted with diethyl ether and washed with a saturated aqueous ammonium chloride solution and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by normal-phase silica gel column chromatography (hexane/ethyl acetate) to afford cyanomethyl 2-(tert-butyldimethylsilyloxy)-3-(tert-butyldisulfanyl)propionate (Compound 25) (48 mg, 71%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([SH:11])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Li]CCCC.Br[CH2:18][CH2:19][C:20]1[O:21][C:22]([CH3:25])=[CH:23][CH:24]=1>C1COCC1>[CH3:25][C:22]1[O:21][C:20]([CH2:19][CH2:18][S:11][C:8]2[CH:9]=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=2)=[CH:24][CH:23]=1
Reactant: CC(=O)Nc1ccc(S)cc1
Reactant: Cc1ccc(CCBr)o1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(SCCc2ccc(C)o2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.6 %

Procedure:
To a solution of 4-acetamidothiophenol (442 mg, 2.64 mmol) in THF (1 mL) at 0° C. under inert atmosphere was added a solution of n-BuLi (2.00 mL, 3.17 mmol, 1.6 M in hexanes) in THF (1 mL). The reaction solution was stirred at room temperature for 10 min then a solution of compound 21B (500 mg, 2.64 mmol) in THF (3 mL) was added. After the starting material was consumed (as determined by TLC), the reaction was quenched with H2O and the mixture was extracted with EtOAc (2×), dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography on silica gel eluting with 50% EtOAc/hexanes gave 0.644 g (2.34 mmol, 88%) of compound 21C. MS (ESI): m/z 276.09 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:13](Cl)(=[O:16])[CH2:14][CH3:15]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([F:8])[CH:5]=[CH:6][C:7]=1[C:13](=[O:16])[CH2:14][CH3:15]
Reactant: Fc1cccc(F)c1
Reactant: CCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCC(=O)c1ccc(F)cc1F
Temperature: 0 °C

Procedure:
To a mixture of m-difluorobenzene (100 ml) and anhydrous aluminium chloride (114 g) was added dropwise, while stirring, propionyl chloride (66 ml), during 45 minutes. The mixture was then stirred for 2 hours on an oil bath of 50°-55° C. The reaction mixture was cooled, to which was added methylene chloride (300 ml). The resultant solution was added by portions to ice-water (11) while stirring. Methylene chloride layer was separated, and the aqueous layer was subjected to extraction twice with methylene chloride (60 ml). Methylene chloride layers were combined and washed with water (200 ml), followed by drying over anhydrous magnesium sulfate. The solvent was distilled off to leave 2',4'-difluoropropiophenone (111.4 g) as a pale yellow oily product. 1H-NMR (CDCl3) δ: 1.17~1.24(3H), 2.92~3.05(2H), 6.82~7.02(2H), 7.89~8.03(1H)
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][N:4]=[C:5]([NH2:16])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9](S(C)=O)[N:8]=1.[H-].[Na+].[OH:21][CH2:22][CH2:23][N:24]1[CH:28]=[CH:27][N:26]=[CH:25]1>C(O)(C)(C)C>[F:1][C:2]([F:18])([F:17])[CH2:3][N:4]=[C:5]([NH2:16])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([O:21][CH2:22][CH2:23][N:24]2[CH:28]=[CH:27][N:26]=[CH:25]2)[N:8]=1
Reactant: CS(=O)c1nccc(NC(N)=NCC(F)(F)F)n1
Reactant: OCCn1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: NC(=NCC(F)(F)F)Nc1ccnc(OCCn2ccnc2)n1

Procedure:
4-[2-(2,2,2-Trifluoroethyl)guanidino]-2-methanesulphinylpyrimidine (140 mg.) was added to a stirred mixture at 50° of t-butanol (10 ml.), NaH (48 mg. of a 50% w/w dispersion in oil) and 1-(2-hydroxyethyl)imidazole, and the mixture stirred at 50° for 2 hours and then evaporated to dryness. The residue was partitioned between aqueous 1N HCl and ether and the aqueous phase basified with aqueous 10N NaOH and extracted with EtOAc. The EtOAc extract was dried and evaporated to dryness and the residue recrystallised from EtOAc to give 1-[2-(4-[2-(2,2,2-trifluoroethyl)guanidino]pyrimid-2-yloxy)ethyl]imidazole (135 mg.), m.p. 149°-150°.
Reaction SMILES: O[C:2]1([CH2:11][NH2:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[ClH:13]>C(O)C>[ClH:13].[CH2:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([CH2:11][NH2:12])=[CH:3]1
Reactant: NCC1(O)CCc2ccccc21
Agent: Cl
Solvent: CCO
Product: NCC1=CCc2ccccc21
Temperature: 25 °C
Yield: 85 %

Procedure:
Two and three-tenth g of 1-hydroxyindanylmethylamine is dissolved in 100 ml of ethanol saturated with HCl . Reaction mixture is refluxed overnight. It is cooled to room temperature and volatiles are evaporated under reduced pressure. The residue is stirred with 300 ml anhydrous ether. Precipitated solid is filtered and dried affording 2.2 g (85%) of the (1H-indene-3-yl)methylamine hydrochloride having a melting point of 245° C. decomp.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=[O:5].Cl[C:13]([O:16]C(=O)OC(Cl)(Cl)Cl)(Cl)Cl>O1CCCC1>[Cl:11][C:7]1[C:3]2[C:4](=[O:6])[O:5][C:13](=[O:16])[NH:1][C:2]=2[CH:10]=[CH:9][CH:8]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1cccc(Cl)c1C(=O)O
Solvent: C1CCOC1
Product: O=c1[nH]c2cccc(Cl)c2c(=O)o1
Temperature: 25 °C
Yield: 250.3 %

Procedure:
To a stirred warm (50° C.) solution of 2-amino-6-chlorobenzoic acid (2.00 g, 11.7 mM) in tetrahydrofuran (20 mL) was added bis(trichloromethyl)carbonate (1.20 g, 4.10 mM). A vigorous gas evolution ensued along with the formation of a precipitate. The reaction mixture was allowed to cool to room temperature and the precipitate was collected by filtration and washed with ether. Air drying gave the title compound as a tan solid (2.0 g, 87%); MS(CI): 198 (M+H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH:34]1[CH2:38][CH2:37][O:36][CH2:35]1>CN(C=O)C>[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH2:33][CH:34]2[CH2:38][CH2:37][O:36][CH2:35]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCNc1nc(N)c2nc(OC)[nH]c2n1
Reactant: BrCCC1CCOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCNc1nc(N)c2nc(OC)n(CCC3CCOC3)c2n1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of N2-butyl-8-methoxy-9H-purine-2,6-diamine trifluoroacetic acid salt, (200 mg) and potassium carbonate (236 mg) in dry DMF (2 mL) were heated at 60° C. with stirring for 1 h. 3-(2-Bromoethyl)tetrahydrofuran, Intermediate 83 (123 mg) was added and the reaction was continued for 2 h at 60° C. The mixture was quenched with water and extracted with EtOAc (×3). The combined organics were washed with water and brine, dried using a hydrophobic frit and evaporated to an oil (261 mg). This material was purified by flash chromatography (silica, 5-20% methanol:ethyl acetate) and the appropriate fractions combined and evaporated to give the title compound, yield 181 mg.