Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl[P:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15]>CCOCC>[C:5]1([CH2:4][CH2:3][P:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: BrCCc1ccccc1
Reactant: CCOP(Cl)OCC
Agent: [Mg]
Solvent: CCOCC
Product: CCOP(CCc1ccccc1)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 4.13 g (0.172 mol) of magnesium in 45 ml of dry ether under argon was treated with a solution of 31.2 g (0.168 mol) of 1-bromo-2-phenylethane (Aldrich) in 90 ml of dry ether, added at a rate that maintained reflux. The reaction was stirred overnight at room temperature under argon, then filtered under argon, cooled to 10° C. and treated with 26.3 g (0.168 mol) of diethyl chlorophosphonite (Aldrich) dissolved in 60 ml of dry ether, added slowly to keep the temperature near 10° C. After addition, the reaction was refluxed for 1 hour, filtered under argon and distilled at 1 atm to remove ether. Vacuum distillation of the residue gave 20.6 g (54%) of the title A compound which distilled at 94°-96° C./0.55 mm Hg. The 1H-NMR and 13C-NMR of this material were both consistent with the assigned structure.
Reaction SMILES: C1(C(C2C=CC=CC=2)=[NH:8])C=CC=CC=1.Br[C:16]1[S:20][C:19]([S:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([OH:42])([CH3:41])[C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=3)[CH2:26][CH2:25]2)(=[O:23])=[O:22])=[CH:18][CH:17]=1.CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[OH-].[Na+]>CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CCOCC.C1(C)C=CC=CC=1>[NH2:8][C:16]1[S:20][C:19]([S:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([OH:42])([CH3:41])[C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=3)[CH2:26][CH2:25]2)(=[O:23])=[O:22])=[CH:18][CH:17]=1
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3ccc(Br)s3)CC2)cc1)C(F)(F)F
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3ccc(N)s3)CC2)cc1)C(F)(F)F
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 48.1 %

Procedure:
A 20-mL vial was charged with 1,1-diphenylmethanimine (0.44 g, 2.40 mmol), 2-(4-(4-((5-bromo-2-thiophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (1.00 g, 2.003 mmol), sodium tert-butoxide (0.46 mL, 4.81 mmol), and 10 mL of toluene. To this was added tris(dibenzylideneacetone)dipalladium (0) (0.18 g, 0.20 mmol, Strem Chemicals, Newburyport, Mass.) and rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) (0.31 g, 0.50 mmol, Sigma-Aldrich, St. Louis, Mo.). The vial was sealed and heated at 80° C. for 12 h. The mixture was then diluted with EtOAc (10 mL) and filtered. The filtrate was concentrated and the dissolved in 15 mL of THF. To this was added 5 M HCl (15.0 mL, 75 mmol). After stirring at room temperature for 30 min, the pH was adjusted to 12 by 5N NaOH. The mixture was extracted with EtOAc, dried with MgSO4, filtered, and concentrated. Purification via column chromatography on silica gel (0-70% EtOAc in hexanes) gave a white foam. To this was added 25 mL of ether and 25 mL of hexanes. The resulting suspension was stirred at room temperature for 5 min. The white solid was collected by filtration to give 2-(4-(4-((5-amino-2-thiophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (0.42 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]2[CH2:8][CH:3]1[CH2:4][NH:5]2.F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:1][N:2]1[CH2:7][CH:6]2[CH2:8][CH:3]1[CH2:4][N:5]2[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CN1CC2CC1CN2
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN1CC2CC1CN2c1ccc([N+](=O)[O-])cc1
Yield: 65.9 %

Procedure:
A solution of 2-methyl-2,5-diaza-bicyclo[2.2.1]heptane (0.4402 g, 1.6 mmol), p-fluoro-nitrobenzene (0.56 mL, 5.4 mmol), N,N-diisopropylethylamine (0.84 mL, 4.82 mmol) in 5 mL of acetonitrile is heated at 100° C. overnight. After the solvent is removed, the residue is treated with saturated sodium bicarbonate solution and extracted with chloroform. The organic layer is washed with brine, dried over magnesium sulfate, filtered, and evaporated to dryness. The oil is washed with hexane to give a yellow solid, which is recrystallized from ethyl acetate/hexane to yield 0.246 g (65% yield) of 2-methyl-5-(4-nitro-phenyl)-2,5-diaza-bicyclo[2.2.1]heptane.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:23](=[O:24])[C:14]3=[CH:15][NH:16][C:17]4[C:22]([N:13]3[C:12]2=[O:25])=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:7][CH:6]=1)(=O)C.Cl>C(O)C>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:23](=[O:24])[C:14]3=[CH:15][NH:16][C:17]4[C:22]([N:13]3[C:12]2=[O:25])=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:7][CH:6]=1
Reactant: CC(=O)Oc1ccc(-n2c(=O)c3c[nH]c4ccccc4n-3c2=O)cc1
Agent: Cl
Solvent: CCO
Product: O=c1c2c[nH]c3ccccc3n-2c(=O)n1-c1ccc(O)cc1
Reaction time: 2 h

Procedure:
2-(4-Acetoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione (250 mg) was added to an ethanol solution (50 mL) saturated with HCl. The solution was stirred for 2 hours and the solvent was removed in vacuo to yield 2-(4-Hydroxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione (Compound 41). m.p. 318-322° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[N:11]([CH2:19][C:20]2[O:21][CH:22]=[CH:23][N:24]=2)[C:10]=1[CH:25]([CH3:27])[CH3:26])=[O:8].Br[C:33]1[S:34][CH:35]=[CH:36][N:37]=1>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][C:33]3[S:34][CH:35]=[CH:36][N:37]=3)=[CH:15][CH:16]=2)[N:11]([CH2:19][C:20]2[O:21][CH:22]=[CH:23][N:24]=2)[C:10]=1[CH:25]([CH3:27])[CH3:26])=[O:8]
Reactant: Brc1nccs1
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(O)cc2n1Cc1ncco1
Solvent: CS(C)=O
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(Oc3nccs3)cc2n1Cc1ncco1

Procedure:
The title compound was prepared from N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1-(oxazol-2-ylmethyl)-1H-indole-3-carboxamide (Compound 210), 2-bromothiazole and DMSO with heating following General Procedure N.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:18]([CH2:27][CH3:28])=[CH:19][C:20]([CH3:26])=[C:21]([CH:25]=3)[C:22]([OH:24])=[O:23])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].S(=O)(=O)(O)O.[CH3:34]O>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[C:18]([CH2:27][CH3:28])=[CH:19][C:20]([CH3:26])=[C:21]([CH:25]=3)[C:22]([O:24][CH3:34])=[O:23])=[O:16])[CH2:13][CH2:14]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CO
Reactant: CCc1cc(C)c(C(=O)O)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Agent: O=S(=O)(O)O
Product: CCc1cc(C)c(C(=O)OC)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a round-bottom flask was added a solution of 5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-4-ethyl-2-methylbenzoic acid (compound 211.6, 600 mg, 1.59 mmol, 1.00 equiv) in methanol (30 mL). To this was added sulfuric acid (500 mg, 5.10 mmol, 3.20 equiv) dropwise. The resulting solution was stiffed for 15 h at 60° C. After cooling to ambient temperature, the mixture was concentrated in vacuo. The residue was diluted with 20 mL of H2O. The aqueous phase was extracted with 3×20 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. This resulted in 500 mg (80%) of methyl 5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-4-ethyl-2-methylbenzoate as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][CH2:14][Cl:15].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[Cl:15][CH2:14][CH2:13][CH2:12][O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(O)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: NC(=O)c1ccc(OCCCCl)cc1

Procedure:
A mixture composed of 0.004 mol of 4-hydroxybenzamide, 0.004 mol of 1-bromo-3-chloropropane and 0.006 mol of caesium carbonate in 10 ml of acetonitrile is heated at reflux for 5 hours.
Reaction SMILES: C(OC([N:8]1[C@@H:14]([C:15](O)=O)[CH2:13][CH2:12][CH2:11][O:10]C1(C)C)=O)(C)(C)C.[C:20]([C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[C:26]([NH2:31])[CH:25]=1)([CH3:23])([CH3:22])[CH3:21]>>[NH2:8][C@@H:14]([C:15]1[NH:30][C:27]2[CH:28]=[CH:29][C:24]([C:20]([CH3:23])([CH3:21])[CH3:22])=[CH:25][C:26]=2[N:31]=1)[CH2:13][CH2:12][CH2:11][OH:10]
Reactant: CC(C)(C)OC(=O)N1[C@@H](C(=O)O)CCCOC1(C)C
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Product: CC(C)(C)c1ccc2[nH]c([C@H](N)CCCO)nc2c1

Procedure:
The title compound was prepared according to Method 4 using (4R)-3-(tert-butoxycarbonyl)-2,2-dimethyl-1,3-oxazepane-4-carboxylic acid (Preparation 48) and 4-tert-butyl-1,2-diaminobenzene.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[F:19][C:20]([F:34])([F:33])[O:21][C:22]1[CH:23]=[C:24](/[CH:28]=[CH:29]/[C:30](O)=[O:31])[CH:25]=[CH:26][CH:27]=1>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:30](=[O:31])/[CH:29]=[CH:28]/[C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([O:21][C:20]([F:33])([F:34])[F:19])[CH:23]=3)[CH:15]=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)/C=C/c1cccc(OC(F)(F)F)c1
Reactant: CC1(c2csc(Cn3ncc(N)n3)n2)OCCO1
Product: CC(=O)c1csc(Cn2ncc(NC(=O)/C=C/c3cccc(OC(F)(F)F)c3)n2)n1

Procedure:
Following general procedure A followed by B, starting from 2-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and (E)-3-(3-trifluoromethoxy-phenyl)-acrylic acid.
Reaction SMILES: N1CC[CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.CC(C)=O.[CH3:18][C:19]([C:21]1[CH:26]=[C:25]([Br:27])[CH:24]=[CH:23][C:22]=1[OH:28])=[O:20]>C1C=CC=CC=1.CCOC(C)=O>[CH3:2][C:3]1([CH3:4])[CH2:18][C:19](=[O:20])[C:21]2[C:22](=[CH:23][CH:24]=[C:25]([Br:27])[CH:26]=2)[O:28]1
Reactant: C1CCNCC1
Reactant: CC(=O)c1cc(Br)ccc1O
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CC(=O)c2cc(Br)ccc2O1
Temperature: 25 °C
Reaction time: 24 h
Yield: 62.2 %

Procedure:
To a solution of piperidine (2,83 g, 33.25 mmol) in 45 mL benzene was added trifluoroacetic acid (344.6 mg, 3.02 mmol) as a solution in 4.0 mL of benzene. Acetone (8.78 g, 151.3 mmol) was added followed by 2-hydroxy-5-bromoacetophenone (Compound 259, 6.50 g, 30.23 mmol). The resulting solution was heated to reflux in a flask fitted with a Dean-Stark trap. After 24 hours, an additional 2.5 equivalents of acetone and 0.1 equivalents of trifluoroacetic acid were added. After a total of 43 hours the reaction was cooled to room temperature and diluted with EtOAc. The solution was washed with 1M aqueous HCl, H2O, and saturated aqueous NaCl before being dried (MgSO4) and concentrated under reduced pressure. Distillation of the residual oil (bulb-to-bulb) afforded 4.80 g (62%) of the title compound as a clear yellow oil, bp 105-115° C./5 mm. The reaction conditions here are a moderate modification of the synthesis of the title compound described by Buckle et al. in J. Med. Chem. 1990 3028-3034. 1H NMR (300 MHz, CDCl3) δ: 7.97 (1H, d, J=2.6 Hz), 7.54 (1H, dd, J=2.6, 8.7 Hz), 6.84 (1H, d, J=8.8 Hz), 2.72 (2H, s), 1.46 (6H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.Cl.[NH:17]1[CH2:21][CH2:20][CH:19]=[CH:18]1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:18]3[N:17]([C:18]4[CH2:19][CH2:20][CH2:21][N:17]=4)[CH2:21][CH2:20][CH:19]=3)[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: Clc1ccc2c(c1)Oc1ccccc1N2
Reactant: C1=CNCC1
Agent: Cl
Product: Clc1ccc2c(c1)Oc1ccccc1N2C1=CCCN1C1=NCCC1

Procedure:
Reaction of 3-chlorophenoxazine with 2-chloro-(1-pyrrolin-;b 2-yl)pyrroline hydrochloride according to the procedure of Example 7 affords 3-CHLORO-10-[1-(1-PYRROLIN-2-YL)-2-PYRROLIN-2-YL]PHENOXAZINE HYDROCHLORIDE, m.p. 262.5°-270° C. (dec.) (corr.), from ethanol-ether.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[C:24]1[CH:29]=[C:28]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][NH:39][C:40]([NH:42][C:43]([CH2:48][OH:49])([CH2:46][OH:47])[CH2:44][OH:45])=[O:41])=[CH:33][CH:32]=2)[C:27]([CH3:50])=[CH:26][C:25]=1[O:51]C(=O)C)(=O)C.C[O-].[Na+]>CO>[OH:47][CH2:46][C:43]([NH:42][C:40]([NH:39][CH2:38][CH2:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][C:28]2[C:27]([CH3:50])=[CH:26][C:25]([OH:51])=[C:24]([C@@H:6]3[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]3[OH:4])[CH:29]=2)=[CH:32][CH:33]=1)=[O:41])([CH2:48][OH:49])[CH2:44][OH:45]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2cc(Cc3ccc(CCNC(=O)NC(CO)(CO)CO)cc3)c(C)cc2OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(O)c([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc(CCNC(=O)NC(CO)(CO)CO)cc1
Temperature: 25 °C
Yield: 52.4 %

Procedure:
To a methanol solution (600 μL) of (1S)-1,5-anhydro-2,3,4,6-tetra-O-acetyl-1-[2-acetoxy-5-[4-[2-[[[[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]amino]carbonyl]amino]ethyl]benzyl]-4-methylphenyl]-D-glucitol (7.9 mg, 0.0104 mmol) was added a 2.5 wt. % methanol solution of sodium methoxide (34 μL, 0.015 mmol), and the mixture was stirred for an hour at room temperature. The solvent was evaporated under reduced pressure. Thus obtained residue was purified with silica gel column chromatography (methanol) to obtain the title compound (3.0 mg, 52%) as a colorless amorphous compound.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[C:13]([NH2:18])=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:6][CH:5]=1)[CH3:3].[H-].[Na+].Cl[CH2:22][CH2:23][S:24](Cl)(=[O:26])=[O:25].C(=O)([O-])O.[Na+]>C1COCC1.C(OCC)(=O)C>[CH3:3][CH:2]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12]2[C:13]3=[N:18][S:24](=[O:26])(=[O:25])[CH2:23][CH2:22][N:14]3[CH:15]=[CH:16][CH:17]=2)=[CH:8][CH:9]=1)[CH3:1]
Reactant: O=S(=O)(Cl)CCCl
Reactant: CC(C)c1ccc(CCc2cccnc2N)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)c1ccc(CCC2=CC=CN3CCS(=O)(=O)N=C23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.2 %

Procedure:
A mixture of 3-{2-[4-(1-methylethyl)phenyl]ethyl}pyridin-2-amine (150 mg) in dehydrated THF (5 mL) was added to a mixture of sodium hydride (60%, 125 mg) and 2-chloroethanesulfonyl chloride (305 mg) in dehydrated THF (5 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 2 hr, and saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added. The resulting precipitate was collected by filtration, and washed with water and ethyl acetate to give the title compound (149 mg) as a white solid. The obtained solid was crystallized from acetonitrile and diisopropyl ether to give a white solid.
Reaction SMILES: N#N.[Cl:3][C:4]1[CH:5]=[C:6]([NH:19][C:20]2[C:21]3[C:28]4[CH:29]=[CH:30][C:31](/[CH:33]=[CH:34]/[C:35]([OH:37])=[O:36])=[CH:32][C:27]=4[S:26][C:22]=3[N:23]=[CH:24][N:25]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1>C1COCC1>[Cl:3][C:4]1[CH:5]=[C:6]([NH:19][C:20]2[C:21]3[C:28]4[CH:29]=[CH:30][C:31]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[CH:32][C:27]=4[S:26][C:22]=3[N:23]=[CH:24][N:25]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1
Reactant: O=C(O)/C=C/c1ccc2c(c1)sc1ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Agent: N#N
Solvent: C1CCOC1
Product: O=C(O)CCc1ccc2c(c1)sc1ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.8 %

Procedure:
Under a blanket of N2 10% Pd—C (4 mg)) was added to a flask which was flushed with N2 and the catalyst was wet with THF. A solution of (2E)-3-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)[1]benzothieno[2,3-d]pyrimidin-7-yl]acrylic acid (40 mg, 0.08 mmol) in THF (2 mL) was also added to the above flask. The flask was vacuumed and H2 was introduced into it. The reaction mixture was stirred under H2 at rt for 16 h. The Pd—C was carefully filtered and the filtrate was concentrated to yield a white solid (30 mg, 75%). 1H-NMR (DMSO-d6) δ 8.95 (s, 1H), 8.50 (s, 1H), 8.45 (d, 1H), 7.96 (s, 1H), 7.74 (d, 1H), 7.52 (dd, 1H), 7.45 (m, 2H), 7.30 (m, 2H), 7.24 (d, 1H), 7.16 (m, 1H), 5.26 (s, 2H), 2.99 (t, 2H), 2.59 (t, 2H); LCMS RT=3.73 min, [M+H]+=508.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][N:11]([CH2:13][Si](C)(C)C)[CH:12]=2)=[CH:4][CH:3]=1.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[N:10][N:11]([CH3:13])[CH:12]=2)=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)Cn1cc(-c2ccc(F)cc2)nn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(-c2ccc(F)cc2)nn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
To a solution of 4-(4-fluoro-phenyl)-1-trimethylsilanylmethyl-1H-[1,2,3]triazole (5.80 g, 23 mmol) in THF (85 mL) was added water (840 μL, 47 mmol) and then tetrabutylammonium fluoride (1 M in THF, 27.9 mL, 28 mmol) was added dropwise at 0° C. The reaction mixture was stirred at 0° C. for 1 h. The resulting mixture was poured into water and then the THF was evaporated. The aqueous layer was then extracted with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 50 to 100% ethyl acetate in heptane) afforded the title compound (4.0 g, 98%) as an off white solid. MS: m/e=178.1 [M+H]+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Al+3].[Cl-].[Cl-].[Cl-].[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16](O)([CH2:18][CH2:19][CH2:20][CH3:21])[CH3:17]>CCOCC>[CH3:17][CH:16]([C:12]1[S:11][CH:15]=[CH:14][CH:13]=1)[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCC(C)(O)c1cccs1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Product: CCCCC(C)c1cccs1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Under nitrogen, a suspension of LiAlH4 (4.9 g, 0.13 mol) in dry Et2O (700 mL) was cooled to 0° C. by an ice/water bath. AlCl3 (34.4 g, 0.26 mol) was then added in small portions. After addition, the mixture was stirred at 0° C. for 1 hour. A solution of 2-thiophen-2-yl-hexan-2-ol in dry Et2O (13.1 g, 70.81 mmol) was then added dropwise. The mixture was stirred at 0° C. for 2 hours, and allowed to warm to room temperature, and stirred at room temperature overnight. After cooling to 0° C., the reaction was quenched by adding water. The reaction mixture was washed with water and brine, dried over Na2SO4, and concentrated on a rotary evaporator. The residue was subjected to column chromatography on silica gel with hexane as the eluent, leading to a colorless oil as the product (6.0 g, 50.3%).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][OH:14])[C:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[O:32][CH:33]=[CH:34][CH:35]=4)[O:28][C:29]=3[CH3:30])=[C:19]([O:36][CH3:37])[CH:18]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4].O1CCCC1>[CH2:1]([N:8]1[CH:12]=[C:11]([CH:13]=[O:14])[C:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[O:32][CH:33]=[CH:34][CH:35]=4)[O:28][C:29]=3[CH3:30])=[C:19]([O:36][CH3:37])[CH:18]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(COc2nn(Cc3ccccc3)cc2CO)ccc1OCc1nc(-c2ccco2)oc1C
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: COc1cc(COc2nn(Cc3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 89.8 %

Procedure:
A mixture of {1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1H-pyrazol-4-yl}methanol (0.95 g), activated manganese dioxide (3.0 g) and tetrahydrofuran (100 mL) was stirred at room temperature for 20 hrs. Manganese dioxide was removed by filtration, and the filtrate was concentrated. The obtained crystals were collected by filtration to give 1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1H-pyrazole-4-carbaldehyde (0.85 g, yield 89%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 139-140° C.
Reaction SMILES: N[C:2]1[S:3][C:4]2[C:9]([NH2:10])=[N:8][CH:7]=[N:6][C:5]=2[N:11]=1.[OH-].[Na+].N([O-])=O.[Na+].[Li+].[Cl-:19]>O>[NH2:10][C:9]1[C:4]2[S:3][C:2]([Cl:19])=[N:11][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: [Cl-]
Reactant: Nc1nc2ncnc(N)c2s1
Agent: O=N[O-]
Agent: [Li+]
Agent: [Na+]
Solvent: O
Product: Nc1ncnc2nc(Cl)sc12
Temperature: 45 °C
Reaction time: 8 h

Procedure:
To a suspension of 2,7-diaminothiazolo[4,5-d]pyrimidine (27: 16.3 g, 97.3 mmol) in water (200 mL) at 55° C. was added enough 1N NaOH (about 100 mL) to dissolve the starting material and sodium nitrite (8.0 g) was then added. This solution was then added dropwise over 30 min. to a solution containing con HC1 (400 mL), water (100 mL) and LiCl (60 g) at 30° C. The resulting mixture was warmed to 45° C. for 15 min. and then hot water (1 L, 90°) was added. The reaction mixture was stirred overnight at room temperature, filtered to remove unreacted starting material and the filtrate was neutralized with solid NaOH to pH 4. The resulting solid was filtered off, washed with water and dried to yield 28: 5.38 g, 34%: recrystallization from water gave an analytical sample: mp>234° C. decomp.: UV λmax (pH 1) 228 nm (ε), 296 () UV λmax (pH 7) 232 nm (ε), 298 (): UV λmax (pH 11) 227 nm (ε), 300 (): 1H NMR (DMSO-d6) δ 7.82 (b, 2H, NH2, exchanges with D2O), 8.41 (s, 1H, C5H). Anal. Calcd. for C5H3N4SC1.0.1H2O: C, 31.87: H, 1.71: N, 29.74: S, 17.02: C1, 18.82. Found: C, 31.71: H, 1.50: N, 29.35: S, 16.92: C1, 19.54.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:31])[C:10]([NH:12][CH2:13][C:14]1[S:18][C:17]([N:19]2[C:23]([C:24](O)=[O:25])=[CH:22][C:21]([C:27]([F:30])([F:29])[F:28])=[N:20]2)=[CH:16][CH:15]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:32]([NH2:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:32]([NH:39][C:24]([C:23]1[N:19]([C:17]2[S:18][C:14]([CH2:13][NH:12][C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH3:31])=[CH:15][CH:16]=2)[N:20]=[C:21]([C:27]([F:28])([F:30])[F:29])[CH:22]=1)=[O:25])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCc1ccc(-n2nc(C(F)(F)F)cc2C(=O)O)s1
Reactant: NCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCc1ccc(-n2nc(C(F)(F)F)cc2C(=O)NCc2ccccc2)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.9 %

Procedure:
To a stirred solution of 25 (45 mg, 0.097 mmol) in CH2Cl2 (0.65 mL) were added benzylamine (0.016 mL, 0.146 mmol), EDC (37.3 mg, 0.195 mmol) followed by DMAP (4.76 mg, 0.039 mmol). The mixture was stirred for 16 h at room temperature. The mixture was quenched with a saturated sodium carbonate solution and extracted with ethyl acetate, washed with brine, dried (MgSO4) filtered and concentrated. The residue was purified by silica gel column chromatography with gradient of EtOAc (20-60%) in hexanes to afford 26a (24 mg, 45%) as a white solid. LRMS (ESI): calc. 551.2; found 574.6 (MNa)+.