Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].[F:8][C:9]([F:21])([F:20])[CH2:10][CH2:11][S:12]([CH2:15][C:16]([O:18][CH3:19])=[O:17])(=[O:14])=[O:13].[H-].[Na+].Cl>CS(C)=O>[F:21][C:9]([F:8])([F:20])[CH2:10][CH2:11][S:12]([CH:15]([CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH2:2])[C:16]([O:18][CH3:19])=[O:17])(=[O:13])=[O:14]
Reactant: COC(=O)CS(=O)(=O)CCC(F)(F)F
Reactant: C=CCCCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: C=CCCCCC(C(=O)OC)S(=O)(=O)CCC(F)(F)F
Temperature: 60 °C
Reaction time: 4 h
Yield: 79.9 %

Procedure:
To a solution of 2.0 g of 6-bromo-1-hexene and 2.9 g of methyl (3,3,3-trifluoropropylsulfonyl)acetate in 50 ml of dimethyl sulfoxide, 0.5 g of sodium hydride (60% in oil) was added at room temperature. The mixture was heated to 60° C., stirred for 4 hours, and then allowed to stand near room temperature. To the reaction mixture, 10% hydrochloric acid was added, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography to obtain 3.10 g of methyl 2-(3,3,3-trifluoropropylsulfonyl)-7-octenoate (hereinafter referred to as the present compound (20)).
Reaction SMILES: [CH3:1][C@@:2]1([CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21](=[O:27])[O:22]C(C)(C)C)[CH2:16][CH2:15]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.FC(F)(F)C(O)=O.[F:35][C:36]([F:46])([F:45])[C:37]1[CH:44]=[CH:43][C:40]([CH2:41]O)=[CH:39][CH:38]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>C(Cl)Cl.CN(C=O)C.O>[CH3:1][C@@:2]1([CH2:13][N:14]2[CH2:15][CH2:16][CH:17]([NH:20][C:21](=[O:27])[O:22][CH2:41][C:40]3[CH:39]=[CH:38][C:37]([C:36]([F:35])([F:45])[F:46])=[CH:44][CH:43]=3)[CH2:18][CH2:19]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1
Reactant: OCc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)NC1CCN(C[C@@]2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: C[C@]1(CN2CCC(NC(=O)OCc3ccc(C(F)(F)F)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.1 %

Procedure:
Tert-butyl (S)-[1-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperidin-4-yl]carbamate prepared in Example 283 (0.300 g, 0.787 mmol) was dissolved in methylene chloride (4 ml). To the solution, trifluoroacetic acid (2 ml) was added followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and added methylene chloride (4 ml) and triethylamine (4 ml). The mixture was stirred at room temperature for 5 minutes and concentrated under reduced pressure. The residue was dissolved in DMF (6 ml). To the solution, a mixture of 4-(trifluoromethyl)benzyl alcohol (0.166 g, 0.944 mmol) in DMF (4 ml) and 1,1′-carbonyldiimidazole (0.153 g, 0.944 mmol) stirred at room temperature for 4 hours was added followed by stirring at room temperature overnight and then at 65° C. for 8 hours. To the reaction mixture, water was added, and the solution was extracted with ethyl acetate twice. The organic phases were combined, washed with water and a saturated saline solution, dried over sodium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/acetone=2/1) and recrystallized from ethyl acetate to afford 4-trifluoromethylbenzyl (S)-[1-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperidin-4-yl]carbamate (0.107 g, yield 28%) as a light yellow powder.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[N:27](COCC[Si](C)(C)C)[C:22]4=[N:23][CH:24]=[CH:25][CH:26]=[C:21]4[N:20]=3)=[CH:14][CH:13]=2)=[N:4]1)[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[CH2:1]([N:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[NH:27][C:22]4=[N:23][CH:24]=[CH:25][CH:26]=[C:21]4[N:20]=3)=[CH:14][CH:13]=2)=[N:4]1)[CH3:2]
Reactant: CCn1nc(-c2ccc(Oc3nc4cccnc4n3COCC[Si](C)(C)C)cc2)c2ncccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCn1nc(-c2ccc(Oc3nc4cccnc4[nH]3)cc2)c2ncccc21
Temperature: 100 °C
Reaction time: 8 h
Yield: 27.3 %

Procedure:
A mixture of 1-ethyl-3-[4-(3-{[2-(trimethylsilyl)ethoxy]methyl}-3H-imidazo[4,5-b]pyridin-2-yloxy)phenyl]-1H-pyrazolo[4,3-b]pyridine (90 mg), 1 M TBAF in THF (0.74 mL) and THF (2 ml) was heated at 100° C. for 3 h under microwave irradiation. The mixture was stirred at 80° C. overnight. The mixture was poured into water and extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (AcOEt/hexane) to give the title compound (18 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[NH:23][CH2:24][C:25]1[CH:29]=[CH:28][S:27][CH:26]=1)[C:7]([N:9]([CH2:15][C:16]([F:19])([F:18])[F:17])[CH2:10][C:11]([F:14])([F:13])[F:12])=[O:8])([O-])=O.O.O.[Sn](Cl)Cl>CN(C=O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[NH:23][CH2:24][C:25]1[CH:29]=[CH:28][S:27][CH:26]=1)[C:7]([N:9]([CH2:15][C:16]([F:17])([F:18])[F:19])[CH2:10][C:11]([F:13])([F:14])[F:12])=[O:8]
Reactant: O=C(c1ccc(NCc2ccsc2)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F
Agent: Cl[Sn]Cl
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(C(=O)N(CC(F)(F)F)CC(F)(F)F)ccc1NCc1ccsc1

Procedure:
Same procedure used as above using 3-nitro-4-[(3-thienylmethyl)amino]-N,N-bis(2,2,2-trifluoroethyl)benzamide (138 mg, 0.312 mmol) and tin(II) chloride dihydrate (210 mg, 0.936 mmol) in 5 mL of DMF. Yield: 125 mg (97%); MS (ESI) 412.08 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:29]=[C:28]([N+:30]([O-])=O)[CH:27]=[CH:26][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH2:16][CH2:15]2)=[O:13])[CH:6]=1.CO>O1CCCC1.[C].[Pd]>[NH2:30][C:28]1[CH:27]=[CH:26][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]3[CH2:19][CH2:18][CH:17]([CH2:20][N:21]4[CH2:22][CH2:23][CH2:24][CH2:25]4)[CH2:16][CH2:15]3)=[O:13])[CH:6]=2)=[C:2]([F:1])[CH:29]=1
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ccn1)N1CCC(CN2CCCC2)CC1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccnc(NC(=O)N3CCC(CN4CCCC4)CC3)c2)c(F)c1
Reaction time: 10 h
Yield: 99.9 %

Procedure:
4-(Pyrrolidin-1-ylmethyl)piperidine-1-carboxylic acid [4-(2-fluoro-4-nitrophenoxy)pyridin-2-yl]amide (290 mg) was dissolved in tetrahydrofuran (7 ml) and methanol (7 ml) under a nitrogen atmosphere, and then 10% palladium carbon (139 mg) was added, followed by stirring under a hydrogen atmosphere for 10 hrs. The reaction mixture was filtered to remove the catalyst, and the catalyst was washed with methanol. The filtrate was concentrated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate). Fractions containing a target compound were concentrated to provide a crude product of 4-(pyrrolidin-1-ylmethyl)piperidine-1-carboxylic acid [4-(4-amino-2-fluorophenoxy)pyridin-2-yl]amide (270 mg) as white foam.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[NH:10][N:11]=[C:12]([I:13])[C:5]=12)[CH3:2].[H-].[Na+].[C:16](Cl)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[CH2:1]([O:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:11]=[C:12]([I:13])[C:5]=12)[CH3:2]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOc1ncnc2[nH]nc(I)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ncnc2c1c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23 %

Procedure:
To a solution of iodo mixture-4-ethoxy-3-iodo-1H-pyrazolo[3,4-d]pyrimidine (1.40 g, 4.823 mmol) in DMF (20 mL) cooled to 0° C., was added NaH (212.2 mg, 5.31 mmol, 60% dispersion in oil). The reaction mixture was stirred at this temperature for 30 minutes and then trityl chloride (1.41 g, 5.06 mmol) was added in one portion. The reaction mixture was allowed to warm to ambient temperature over 18 hours. After this time, the reaction mixture was concentrated in vacuo, diluted with DCM and water. The organic layer was separated and washed with saturated aqueous brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude mixture was purified by column chromatography (ISCO Companion™, 120 g column, eluting with DCM) to give the sub title compound as a mixture of regioisomers (592 mg, 23% Yield). 1H NMR (400 MHz, DMSO) δ 8.27 (1H, s), 7.34-7.12 (15H, m), 4.55 (3H, q) and 1.40 (2H, t).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](I)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[F:19][C:20]1([F:26])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N:23]3[CH2:24][CH2:25][C:20]([F:26])([F:19])[CH2:21][CH2:22]3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: FC1(F)CCNCC1
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(I)cc2C1
Agent: Cl
Product: CC(C)(C)OC(=O)N1Cc2ccc(N3CCC(F)(F)CC3)cc2C1

Procedure:
Prepared in analogy to Example A3(d) from 5-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A38(b)) and 4,4-difluoropiperidine hydrochloride. Yellow solid. MS (m/e): 339.1 ([M+H]+, 100%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[CH2:10][CH:11]2[OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].C1(C)C=CC=CC=1.Br[CH2:26][CH2:27][O:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][O:30]1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[CH2:10][CH:11]2[O:15][CH2:26][CH2:27][O:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][O:30]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2CC1CC2O
Reactant: BrCCOC1CCCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC2CC1CC2OCCOC1CCCCO1
Temperature: 60 °C
Reaction time: 8 h
Yield: 45.2 %

Procedure:
Tert-butyl-5-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate (1.5 g, 7.0 mmol) and tetrabutylammonium bromide (0.35 g, 0.70 mmol) were stirred in sodium hydroxide (10 M) (30 mL, 1600 mmol)/toluene (30 mL) and heated to 60° C. 2-(2-Bromoethoxy)tetrahydropyran (4.4 g, 21 mmol) was added in 4 portions over 2 hours and heating continued overnight. Further 2-(2-bromoethoxy)tetrahydropyran (1 eq) was added and the reaction heated for a further 3 hours. The reaction mixture was diluted with DCM, washed with water, dried over Na2SO4 and concentrated in vacuo to afford a yellow oil. The reaction mixture was purified by flash chromatography, eluting with DCM then 90/10 DCM/MeOH to afford tert-butyl-5-(2-tetrahydropyran-2-yloxyethoxy)-2-azabicyclo[2.2.1]heptane-2-carboxylate (1.08 g).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2O)[N:5]=[C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:37]([O:44][CH2:45][C@@H:46]([OH:48])[CH3:47])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CO.O>[CH2:37]([O:44][CH2:45][C@@H:46]([CH3:47])[O:48][C:9]1[CH:8]=[C:7]([N:6]2[C:2]([NH2:1])=[CH:3][C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])=[N:5]2)[CH:12]=[CH:11][CH:10]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: C[C@H](O)COCc1ccccc1
Reactant: CC(C)(C)c1cc(N)n(-c2ccccc2O)n1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](COCc1ccccc1)Oc1cccc(-n2nc(C(C)(C)C)cc2N)c1
Temperature: 0 °C
Reaction time: 1.75 h
Yield: 44.3 %

Procedure:
A mixture of Intermediate 95a (0.50 g, 2.2 mmol) in dry THF (17 mL) was treated with triphenylphosphine (1.13 g, 4.32 mmol) and (S)-(+)-1-Benzyloxy-2-propanol (0.52 mL, 3.24 mmol). The mixture was cooled to 0° C. then diisopropylazodicarboxylate (0.85 mL, 4.32 mmol) was added dropwise. After stirring at ambient temperature for 1.75 h the mixture was treated with water (0.2 mL) then applied to a pre-conditioned (with MeOH) SCX-2 cartridge. The cartridge was eluted with MeOH then 2N NH3 in MeOH. The product containing fractions were combined and concentrated in vacuo to a viscous brown oil. The oil was purified by FCC, using 0-30% EtOAc in cyclohexane, to give the title compound as a golden oil (0.37 g, 45%). LCMS (Method 3): Rt 3.71 min, m/z 380.3 [MH+].
Reaction SMILES: [H-].[Na+].C(OC(C)(C)C)(=O)[CH2:4][C:5]([O:7]C(C)(C)C)=[O:6].[F:18][C:19]1[C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23]([F:29])[C:22]([F:30])=[C:21](F)[C:20]=1[F:32].Cl>CN(C)C=O.FC(F)(F)C(O)=O.C1(C)C=CC=CC=1.O.C(OCC)C.C(OCC)(=O)C>[C:5]([CH2:4][C:21]1[C:22]([F:30])=[C:23]([F:29])[C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:19]([F:18])[C:20]=1[F:32])([OH:7])=[O:6]
Reactant: COC(=O)c1c(F)c(F)c(F)c(F)c1F
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1c(F)c(F)c(CC(=O)O)c(F)c1F
Reaction time: 0.17 h
Yield: 55.4 %

Procedure:
In 500 ml of N,N-dimethylformamide was suspended 10.2 g of 60% sodium hydride. Thereinto was dropped 55.0 g of di-tert-butyl malonate in 1 hour with ice-cooling. The resulting mixture was stirred for 10 minutes at the same temperature. Thereto was added 48.0 g of methyl pentafluorbenzoate. The resulting mixture was stirred for 2 hours at room temperature. The reaction mixture was added to a mixture of 1 liter of water and 400 ml of ethyl acetate. The resulting mixture was adjusted to pH 3 with 6N hydrochloric acid. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue obtained was dissolved in 150 ml of trifluoroacetic acid. The resulting solution was stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure. To the residue obtained were added 200 ml of diethyl ether and 600 ml of water in this order. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. To the residue obtained was added 50 ml of toluene. The resulting mixture was refluxed for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and n-hexane was added to the residue obtained. The resulting crystals were collected by filtration to obtain 31.3 g (yield: 55.5%) of methyl 4-carboxymethyl-2,3,5,6-tetrafluorobenzoate.
Reaction SMILES: Br[CH2:2][C:3](=[O:26])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C@@H:11]([CH2:12][C@:13]([C:24]#[CH:25])([OH:23])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.[SH:27][CH2:28][CH2:29][OH:30].C(N(CC)CC)C.CCCCCC.CC(C)=O>C1COCC1>[C:24]([C@@:13]1([OH:23])[CH2:14][CH2:15][C@@:16]2([CH3:17])[C@H:11]([CH2:10][CH2:9][C@@H:8]3[C@@H:18]2[CH2:19][CH2:20][C@@:21]2([CH3:22])[C@H:7]3[CH2:6][CH2:5][C@@H:4]2[C:3](=[O:26])[CH2:2][S:27][CH2:28][CH2:29][OH:30])[CH2:12]1)#[CH:25]
Reactant: C#C[C@@]1(O)CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C(=O)CBr)CC[C@@H]32)C1
Reactant: OCCS
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#C[C@@]1(O)CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C(=O)CSCCO)CC[C@@H]32)C1

Procedure:
A solution of 21-bromo-3β-ethynyl-3α-hydroxy-5β-pregnan-20-one (150 mg, 0.356 mmol), 2-mercaptoethanol (31 μL, 0.445 mmol), and triethylamine (62 μL, 0.445 mmol) in 5 mL of THF was stirred at room temperature overnight. The mixture was partitioned between EtOAc and water. The organic layer was washed with sat. aq. NaCl, dried with Na2SO4 and concentrated in vacuo resulting in 3β-ethynyl-3α-hydroxy-21-hydroxyethylthio-5β-pregnan-20-one (141 mg) as a white solid; mp 122-126° C.; TLC Rf (hexane:acetone 3:1)=0.11.
Reaction SMILES: [OH:1][CH:2]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10]>CC(C)=O.[O-2].[Mn+4].[O-2]>[CH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:19]=[CH:20][C:11]=1[C:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10])=[O:1]
Reactant: OCCCCCCCC(O)c1ccc2ccccc2c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(C)=O
Product: O=C(CCCCCCCO)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.8 %

Procedure:
To a solution of 1-hydroxy-1-[(2-naphthyl)]-8-octanol 70 (715 mg, 2.63 mmol) in acetone (25 mL) was added manganese (IV) oxide (7.0 g, 81 mmol) and the reaction mixture was stirred at room temperature for 16 hours. The mixture was filtered through a short pad of Celite and the solvents were removed in vacuo. The title compound 71 (361 mg, 51%) was isolated by column chromatography (4:6 ethyl acetate:hexane). 1H NMR (400 MHz, DMSO-d6): δ 8.68 (s, 1H), 8.11 (d, 1H), 8.00 (m, 3H), 7.64 (m, 2H), 4.32 (t, 1H), 3.15 (t, J=7.2 Hz, 2H), 1.67 (m, 2H), 1.40 (m, 2H), 1.32 (m, 8H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]#[N:5].C(N(CC)CC)C.[N+:13]([C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1)([O-:15])=[O:14]>C(Cl)(Cl)Cl>[C:4]([CH2:3][NH:2][C:20](=[O:21])[C:19]1[CH:18]=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:24][CH:23]=1)#[N:5]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: N#CCN
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: N#CCNC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
To a stirred mixture of 9.3 g (0.1 mole) aminoacetonitrile hydrochloride in 200 ml chloroform, 20.2 g (0.2 moles) triethylamine were added at once. After stirring one hour, 18.6 g (0.1 mole) p-nitrobenzoyl chloride were added in portions over about 15 minutes. The reaction mixture was stirred about 11/2 hours. Ice water, 100 ml, was added, resulting in separation of solids. The reaction mixture was allowed to stand in an ice bath for 30 minutes and then was filtered. The solids were air dried, washed with 200 ml water and then filtered to give yellow solids. The solids were dried in a vacuum oven at 50° C. until constant weight was attained, yielding 18.0 g of the above-identified product as a light yellow solid, melting point 147° C. to 149° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]([O:17][CH:18]([CH3:20])[CH3:19])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:2]1.[H-].[Na+].Br[CH2:24][C:25]([O:27]C(C)(C)C)=[O:26].[Cl-].[NH4+]>CN(C)C=O.O>[C:25]([CH2:24][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]([O:17][CH:18]([CH3:19])[CH3:20])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:2]1)([OH:27])=[O:26]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCOC(=O)C(Cc1c[nH]c2ccccc12)OC(C)C
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1cn(CC(=O)O)c2ccccc12)OC(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.75 g of Ethyl 3-(1H-indol-3-yl)-2-isopropoxypropionate was dissolved in 10 ml of N,N-dimethylformamide, and 0.12 g of 60% sodium hydride was added under ice-cooling. The reaction mixture was stirred at room temperature for 30 minutes, 0.53 ml of t-butyl bromoacetate was added, and stirring was continued at room temperature for 16 hours. The reaction solution was cooled with ice, treated with water and ammonium chloride solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was subjected to silica gel column chromatography, and the fraction eluted with 10% ethyl acetate-hexane was evaporated, and the residue was dissolved in 15 ml of dichloromethane. 3 ml of Trifluoroacetic acid was added under ice-cooling, and the mixture was stirred at 0° C. for 7 hours. The reaction solution was diluted with toluene, and the solvent was evaporated. The residue was subjected to silica gel column chromatography (33% ethyl acetate-hexane), to give 0.3 g of the title compound.
Reaction SMILES: O(P(O[C:18]1[N:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=1)(OC1C=CC=CC=1)=O)C1C=CC=CC=1.B([C:34]1[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[CH:36][CH:35]=1)(O)O>>[C:27]([O:26][C:24]([N:19]1[C:18]([C:34]2[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[CH:36][CH:35]=2)=[CH:23][O:22][CH2:21][CH2:20]1)=[O:25])([CH3:28])([CH3:29])[CH3:30]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCOC=C1OP(=O)(Oc1ccccc1)Oc1ccccc1
Product: CC(C)(C)OC(=O)N1CCOC=C1c1ccc(C(=O)O)cc1
Yield: 30 %

Procedure:
This compound was prepared from tert-butyl 5-((diphenoxyphosphoryl)oxy)-2H-1,4-oxazine-4(3H)-carboxylate and 4-boronobenzoic acid using a procedure similar to that described in Example 2 (Steps 1-3a) above. The product was isolated as an off-white solid (30% yield); 1H-NMR (d6-DMSO) 1.06 (9H, s), 3.69 (2H, t), 4.12 (2H, t), 6.58 (1H, s), 7.29 (2H, d), 7.85 (2H, d), 12.83 (1H, brs); 13C-NMR (CDCl3); 27.7, 41.3, 66.8, 124.5, 130.1, 134.0; MS ES(+) 249.9 (M+-tBu). IR λmax=1701, 1674 cm−1.
Reaction SMILES: [OH:1][C@H:2]([CH3:6])[C:3]([NH2:5])=O.F[B-](F)(F)F.C([O+](CC)CC)C.N[C:20]1[C:21]([NH:29][C@@H:30]2[CH2:35][CH2:34][C@H:33]([C:36]#[N:37])[CH2:32][CH2:31]2)=[C:22]2[S:28][CH:27]=[CH:26][C:23]2=[N:24][CH:25]=1>O1CCCC1.C(O)C>[OH:1][C@@H:2]([C:3]1[N:29]([C@@H:30]2[CH2:31][CH2:32][C@H:33]([C:36]#[N:37])[CH2:34][CH2:35]2)[C:21]2=[C:22]3[S:28][CH:27]=[CH:26][C:23]3=[N:24][CH:25]=[C:20]2[N:5]=1)[CH3:6]
Reactant: C[C@@H](O)C(N)=O
Reactant: N#C[C@H]1CC[C@@H](Nc2c(N)cnc3ccsc23)CC1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: C1CCOC1
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@@H](C#N)CC1
Reaction time: 0.25 h

Procedure:
A mixture of (2R)-2-hydroxypropanamide (40 mg, 0.4 mmol) and triethyloxonium tetrafluoroborate (89 mg, 0.47 mmol) in tetrahydrofuran (0.4 mL) became a solution after stirring for 15 min. After another 45 min, this solution was added to a mixture of cis-4-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]cyclohexanecarbonitrile (32 mg, 0.12 mmol) in ethanol (0.74 mL) and heated at reflux overnight. The resulting mixture was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (1.1 mg, 2.9%). LCMS calculated for C17H19N4OS (M+H)+: m/z=327.1. Found: 327.0.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14].[Br:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Br>CCOCC>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([CH2:29][C:28]1[CH:31]=[CH:32][CH:33]=[C:26]([Br:25])[CH:27]=1)[S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14]
Reactant: BrCc1cccc(Br)c1
Reactant: COC(=O)c1cc(C)cc(C)c1NS(=O)(=O)c1ccc(OC)cc1
Solvent: CCOCC
Product: COC(=O)c1cc(C)cc(C)c1N(Cc1cccc(Br)c1)S(=O)(=O)c1ccc(OC)cc1
Yield: 92 %

Procedure:
In the same manner as described in Example 9, 0.699 g (2.0 mmol) of the product of Example 62 and 0.6 g (2.4 nunol) of m-bromobenzyl bromide provided 0.954 g (92%) of the desired product as a white solid after trituration with ether. Electrospray Mass Spec 518.1 (M+H).