Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:14]=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=5[C:27]([F:30])([F:29])[F:28])=[CH:17][CH:16]=4)[O:12][N:11]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(OC1C=C(C2ON=C(C3C=CC=C4C=3C=CN4)N=2)C=CC=1OCC)C>>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:14]=[C:13]([C:15]4[CH:16]=[CH:17][C:18]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=5[C:27]([F:30])([F:28])[F:29])=[CH:19][CH:20]=4)[O:12][N:11]=3)[CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: FC(F)(F)c1ccccc1-c1ccc(-c2nc(-c3cccc4[nH]ccc34)no2)cc1
Agent: CCOc1ccc(-c2nc(-c3cccc4[nH]ccc34)no2)cc1OCC
Product: FC(F)(F)c1ccccc1-c1ccc(-c2nc(-c3cccc4c3CCN4)no2)cc1
Yield: 99 %

Procedure:
When the product of Step C is substituted for 5-(3,4-diethoxyphenyl)-3-(1H-indol-4-yl)-1,2,4-oxadiazole in Example 34, Step C, the identical process afforded the title compound in 99% yield., as a colourless foam. 1H-NMR (CDCl3) 3.49 (tr, 2H, J=8.7 Hz); 3.66 (tr, 2H, J=8.7 Hz); 4.09 (broad s, 1H); 6.76 (d, 1H, J=7.6 Hz); 7.16 (tr, 1H, J=7.2 Hz); 7.34 (d, 1H, J=7.6 Hz); 7.4-7.63 (m, 5H); 7.77 (d, 1H, J=7.6 Hz); 8.24 (d, 1H, J=8.5 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:13][CH:12]2[CH:8]([CH2:9][C:10]3[C:16]([CH2:17][OH:18])=[CH:15][S:14][C:11]=32)[CH2:7]1)=[O:5])[CH3:2].C(Cl)(Cl)[Cl:20]>C(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[CH2:13][CH:12]2[CH:8]([CH2:9][C:10]3[C:16]([CH2:17][OH:18])=[C:15]([Cl:20])[S:14][C:11]=32)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CC2Cc3c(CO)csc3C2C1
Reactant: ClC(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)N1CC2Cc3c(sc(Cl)c3CO)C2C1
Reaction time: 1 h
Yield: 45 %

Procedure:
The product of step c) (185 mg, 0.74 mmol) was dissolved in CHCl3 (2.7 ml) and a solution of SO2Cl2 (59.5 μl, 0.74 mmol) in CHCl3 (1 ml) was added dropwise over 10 minutes and the contents were stirred for 1 hour. Next, the mixture was diluted with CH2Cl2 (10 ml), washed with H2O (2×25 ml), sat. NaHCO3 (25 ml) and dried (MgSO4). The crude residue was purified by preparative TLC (hexanes/EtOAc-1:3) to give the subtitle compound (99.7 mg, 45%). 1H NMR (300 MHz, CDCl3, ppm) 1.20 (t, J=7 Hz, 3H); 2.37 (br s, 1H); 2.65-2.71 (m, 1H); 2.90-3.05 (m, 1H); 3.08-3.18 (br m, 1H); 3.28-3.42 (br m, 1H); 3.52-3.72 (br m, 2H); 3.75-3.88 (m, 2H); 4.09 (q, J=7 Hz, 2H); 4.54 (s, 2H).
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH:17]2[CH:24]3[CH2:25][CH:20]4[CH2:21][CH:22]([CH2:26][CH:18]2[CH2:19]4)[CH2:23]3)=[O:15])[CH2:10]1)=O)(C)(C)C.[ClH:27].O1CCOCC1>>[ClH:27].[NH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH:17]2[CH:18]3[CH2:19][CH:20]4[CH2:21][CH:22]([CH2:23][CH:24]2[CH2:25]4)[CH2:26]3)=[O:15])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(C(=O)OC2C3CC4CC(C3)CC2C4)C1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H]1CCN(C(=O)OC2C3CC4CC(C3)CC2C4)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To (3R)-(2-adamantyl) 3-(tert-butoxycarbonylamino)pyrrolidine-1-carboxylate (0.43 g, 1.18 mmol) was added 4 M HCl in dioxane (5 mL, 20 mmol). The mixture was stirred at rt for 1 h and concentrated to afford (R)-2-adamantyl 3-aminopyrrolidine-1-carboxylate HCl salt (0.45 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[N:16]1([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:1][C:2]1[C:3]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[C:4]([CH2:5][N:19]2[CH2:18][CH2:17][N:16]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20]2)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1cccc(C=O)c1N1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: Cc1cccc(CN2CCN(C(=O)OC(C)(C)C)CC2)c1N1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.7 %

Procedure:
A 100 mL round-bottom flask was charged with 3-methyl-2-(morpholin-4-yl)benzaldehyde (1.34 g, 6.51 mmol, 1.00 equiv), tert-butyl piperazine-1-carboxylate (1.00 g, 5.37 mmol, 0.82 equiv), 1,2-dichloromethane (30 mL). The mixture was stirred at room temperature for 0.5 hour. Sodium triacetoxyborohydride (3.42 g, 16.1 mmol, 2.48 equiv) was added. The resulting solution was stirred for 2 h at room temperature and diluted with 1,2-dichloromethane (30 mL). The resulting solution was washed with H2O (2×30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/3) to provide 0.800 g (34% yield) of tert-butyl 4-[[3-methyl-2-(morpholin-4-yl)phenyl]methyl]piperazine-1-carboxylate as light red oil. LCMS (ESI, m/z): 396 [M+H]+.
Reaction SMILES: [O:1]=[C:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14])[C:3]([OH:5])=[O:4].[BH4-].[Na+].Cl>O.C(O)CCCCCCCCC>[OH:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14])[C:3]([OH:5])=[O:4]
Reactant: O=C(O)C(=O)Cc1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCCCCCCO
Product: O=C(O)C(O)Cc1ccccc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
To a magnetically stirred suspension of α-oxo-2-nitrobenzenepropanoic acid (5.00 g) in water (75 ml) containing 1 drop of decyl alcohol was added sodium borohydride (2.50 g) in portions to maintain a temperature between 45 and 50°. The resulting solution was then left at room temperature for 21/2 hours. The solution was acidified with concentrated hydrochloric acid and seeded. Stirring and cooling gave crude product; yield 5.01 g, m.p. 84°-90°. Recrystallization from water gave titled product; yield 2.63 g (52%), m.p. 95°-98° with spectral data as above.
Reaction SMILES: [CH:1]1(O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:26](C(OC(C)(C)C)=O)=[N:27]C(OC(C)(C)C)=O.[ClH:42].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>O1CCCC1.O>[ClH:42].[ClH:42].[CH:1]1([NH:26][NH2:27])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCC1
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NNC1CCCC1
Temperature: 5 °C
Reaction time: 5 h

Procedure:
Cyclopentanol (6.127 kg, 71.1 moles) and triphenylphosphine (18.667 kg, 71.25 moles) were dissolved in tetrahydrofuran (40 gal) in a clean and dry, nitrogen purged 100 gallon tank and the reaction mixture was cooled to 5° C. A solution of di-t-butyl azodicarboxylate (14.9 kg, 64.7 moles) in tetrahydrofuran (36 L) was added over about 2 hours keeping the temperature <6° C. The reaction was allowed to stir for 5 hours as the temperature was allowed to slowly increase to 20-25° C. 6N HCl (26.5 L) was added to the reaction which was at 20° C. The reaction was allowed to stir 24 hours at 20-25° C. at which point the starting material had reacted. Water (10 gal, 37.85 L) was added and the tetrahydrofuran was removed by vacuum distillation. During the concentration, triphenylphosphine oxide precipitated and an additional 20 gal (75.7 L) of water was added. The reaction was cooled and methylene chloride (30 gal, 113.6 L) was added. The layers were separated and the aqueous was extracted twice more with methylene chloride (10 gal, 37.85 L) The aqueous was distilled to remove water. As the volume was reduced, isopropanol (3×20 gal (75.7 L)) was added to azeotrope the residual water. The resulting slurry was filtered and the solids were vacuum oven dried to give 7.682 kg (68.6% of theoretical) over multiple crops. This material was characterized to be the dihydrochloride salt; mp 189-194° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[O:8][C:7](=[O:15])[C:6]=2[CH:16]=1.II>CC(C)=O>[CH3:6][C:5]1([CH3:14])[CH:4]=[C:3]([CH3:2])[C:16]2[C:2](=[CH:3][CH:4]=[C:5]3[C:6]=2[C:7](=[O:15])[O:8][C:9]2[C:14]3=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:1]1
Reactant: Nc1ccc2c(c1)c(=O)oc1ccccc12
Agent: II
Solvent: CC(C)=O
Product: CC1=CC(C)(C)Nc2ccc3c(c21)c(=O)oc1ccccc13
Temperature: 105 °C
Reaction time: 48 h
Yield: 40 %

Procedure:
In a pressure tube, 8-aminobenzo[c]chromen-6-one (Reference Compound No. 1-1-(2), 8.81 g, 41.7 mmol) was dissolved in acetone (300 mL), then iodine (4.24 g, 16.7 mmol) was added thereto, then the pressure tube was sealed, and then the reaction mixture was stirred at 105° C. for 2 days. After cooling down, the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (4.83 g) as a yellow solid. (Yield 40%)
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][C:14](=[O:16])[CH3:15])[N:7]=1)(=[O:5])[CH3:4].[BrH:17].C(O)(=O)C>C(O)(=O)C.CO>[BrH:1].[C:14]([NH:13][CH2:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([C:3](=[O:5])[CH2:4][Br:17])[N:7]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)NCc1cccc(C(C)=O)n1
Reactant: BrBr
Agent: Br
Solvent: CC(=O)O
Solvent: CO
Product: CC(=O)NCc1cccc(C(=O)CBr)n1

Procedure:
A solution of bromine (1.56 g) in acetic acid (5 ml) was added dropwise to a solution of 2-acetyl-6-(acetylaminomethyl)pyridine (1.87 g) and 30 weight % hydrogen bromide-acetic acid solution (4.2 ml) in a mixture of acetic acid (40 ml) and methanol (10 ml) at ambient temperature with stirring. The mixture was warmed to 60° to 70° C. and stirred for two hours. The solvent was evaporated in vacuo and the residue was triturated with diisopropyl ether to give 2-(acetylaminomethyl)-6-bromoacetylpyridine hydrobromide (3.78 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[S:8][CH:7]1[CH3:14].[ClH:15].[S:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[N:17]1.S1C2C=CC=CC=2C(N2CCNCC2)=N1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>C(#N)C>[ClH:15].[S:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18]([N:25]2[CH2:26][CH2:27][N:28]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[S:8][CH:7]3[CH3:14])[CH2:29][CH2:30]2)=[N:17]1
Reactant: CC1SC(C)(C)C(=O)N1CCCCBr
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: CC1SC(C)(C)C(=O)N1CCCCN1CCN(c2nsc3ccccc23)CC1
Temperature: 65 °C
Yield: 61.3 %

Procedure:
A mixture of 3-(4-bromobutyl)-2,5,5-trimethyl-4-thiazolidinone (4.70 g), 1-(1,2-benzisothiazol-3-yl)piperazine 1-(1,2-benzisothiazol-3-yl)piperazine hydrochloride (4.72 g), K2CO3 (8.13 g) and NaI (300 mg) in acetonitrile (200 ml) was heated at 65° C. for 16 hours and the product was processed in substantially the same manner as in Example 10 to afford 2.77 g of crystals, m.p. 209°-214° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[C:19](F)[C:18](Cl)=[CH:17][C:16]=2[C:23]2[N:27]([CH3:28])[C:26]([CH2:29][CH3:30])=[N:25][N:24]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:31]([Cu])#[N:32].CN(C=O)C>CCOC(C)=O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:31]#[N:32])=[CH:17][C:16]=2[C:23]2[N:27]([CH3:28])[C:26]([CH2:29][CH3:30])=[N:25][N:24]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1nnc(-c2cc(Cl)c(F)cc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n1C
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1nnc(-c2cc(C#N)ccc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n1C
Temperature: 100 °C
Reaction time: 48 h

Procedure:
A 4 mL scintillation vial was charged with 4-tert-butyl-N-[4-iodo-2-(5-ethyl-4-methyl-4H-[1,2,4]triazol-3-yl)-phenyl]-benzenesulfonamide (prepared according to general procedure C, 18 mg, 0.034 mmol), CuCN (15 mg, 0.17 mmol), and DMF (500 μL). The reaction was then heated to 100° C. and stirred for 48 hours. The solution was then diluted with EtOAc and washed with an aqueous solution of EDTA (5% wt/wt). The organic layer was then concentrated and the residue purified by preparative TLC to afford 4-tert-butyl-N-[4-cyano-2-(5-ethyl-4-methyl-4H-[1,2,4]triazol-3-yl)-phenyl]-benzenesulfonamide as a white solid: MS (ES) M+H expected 424.2, found 424.4.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24]>CC#N.CN(C=O)C>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)CN
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC#N
Product: COC(=O)CNC1=C(c2ccccc2)S(=O)(=O)N(C(C)(C)C)C1=O
Temperature: 65 °C

Procedure:
2-tert-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (1.09 g, 3.64 mmol), methyl glycinate hydrochloride (0.68 g, 5.46 mmol) and TEA (10.10 g, 10.92 mmol) were dissolved in a mixture of MeCN (10 mL) and DMF (5 mL) and the reaction mixture was stirred at 65° C. over night. The reaction mixture was evaporated and the residue was diluted with saturated aqueous NaHCO3 and the mixture was extracted with DCM. The organic phases were combined, dried over MgSO4, filtered and evaporated to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[C:15]([CH:16]=[CH:17][CH:18]=1)=[C:14]([C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[F:28])[C:22]([OH:24])=[O:23])[C:13](=[O:29])[CH:12]=[CH:11]2.[C:30](Cl)(=O)C(Cl)=O>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[C:15]([CH:16]=[CH:17][CH:18]=1)=[C:14]([C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[F:28])[C:22]([O:24][CH3:30])=[O:23])[C:13](=[O:29])[CH:12]=[CH:11]2
Reactant: O=C(O)c1ccc(F)c(-c2c(=O)ccn3c(-c4ccc(F)cc4F)cccc23)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CO
Product: COC(=O)c1ccc(F)c(-c2c(=O)ccn3c(-c4ccc(F)cc4F)cccc23)c1
Temperature: 25 °C

Procedure:
To a solution of 3-[6-(2,4-difluorophenyl)-2-oxo-2H-quinolizin-1-yl]-4-fluorobenzoic acid (Example 31, 15 mg, 0.04 mmol) in MeOH (2 mL) was added oxalyl chloride dropwise at 0° C. The reaction mixture was allowed to warm to ambient temperature for 12 h. The mixture was concentrated and the crude material was purified via silica gel chromatography (100% EtOAc).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH:15]2[C:24]3[N:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH2:18][CH2:17][CH2:16]2)[CH2:11][CH2:12][CH2:13][NH2:14])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.CCN(CC)CC.[CH3:32][C:33](OC(C)=O)=[O:34]>C(Cl)Cl>[CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH:15]2[C:24]3[N:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH2:18][CH2:17][CH2:16]2)[CH2:11][CH2:12][CH2:13][NH:14][C:33](=[O:34])[CH3:32])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cnc(CN(CCCN)C2CCCc3cccnc32)c(C)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCCCN(Cc1ncc(C)cc1C)C1CCCc2cccnc21
Yield: 71.2 %

Procedure:
To a solution of N1-(3,5-Dimethyl-pyridin-2-ylmethyl)-N1-(5,6,7,8-tetrahydro-quinolin-8-yl)-propane-1,3-diamine (78 mg, 0.23 mmol) in CH2Cl2 (2.5 mL) was added Et3N (100 μL, 0.72 mmol) followed by Ac2O (40 μL, 0.43 mmol). The resultant solution was stirred at room temperature for 45 minutes. The mixture was diluted with CH2Cl2 (20 mL), washed with brine (3×5 mL), dried (Na2SO4), and concentrated. Purification of the crude material by column chromatography on silica gel (20:1:1 CH2Cl2-MeOH—NH4OH) provided 60 mg (71%) of the free base of the title compound as a white foam. Conversion of the foam to the HBr salt gave COMPOUND 362 as a white solid. 1H NMR (D2O) δ 1.42-1.47 (m, 2H), 1.71-1.80 (m, 4H), 1.99-2.17 (m, 2H), 2.32-2.39 (m, 2H), 2.41 (s, 3H), 2.45 (s, 3H), 2.62-2.72 (m, 1H), 2.92-2.97 (m, 4H), 4.11 (d, 1H, J=17.1 Hz), 4.33 (d, 1H, J=17.1 Hz), 4.45 (dd, 1H, J=10.5, 5.7 Hz), 7.84 (dd, 1H, J=8.1, 5.4 Hz), 8.19 (s, 1H), 8.32 (d, 1H, J=8.1 Hz), 8.42 (s, 1H), 8.57 (d, 1H, J=5.4 Hz); 13C NMR (D2O) δ 17.13, 17.56, 20.45, 20.65, 22.17, 27.85, 28.05, 37.58, 49.78, 52.00, 61.10, 125.88, 136.64, 137.42, 137.79, 139.39, 140.75, 148.15, 148.73, 149.28, 151.16, 174.37; ES-MS m/z 367 (M+H). Anal. Calcd. For C22H30N4O.2.9HBr.3.7H2O: C, 39.57; H, 6.08; N, 8.39; Br, 34.70. Found: C, 39.62; H, 5.85; N, 8.04; Br, 34.70.
Reaction SMILES: [P:1]([O-:39])([O:35][CH2:36][CH2:37]Br)([O:3][CH2:4][CH:5]([O:29][C:30]1[CH:34]=[CH:33][O:32][N:31]=1)[CH2:6][O:7][C:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[O:10][N:9]=1)=[O:2].[CH3:40][N:41]1[CH:45]=[CH:44][N:43]=[CH:42]1>>[P:1]([O-:39])([O:35][CH2:36][CH2:37][N+:43]1[CH:44]=[CH:45][N:41]([CH3:40])[CH:42]=1)([O:3][CH2:4][CH:5]([O:29][C:30]1[CH:34]=[CH:33][O:32][N:31]=1)[CH2:6][O:7][C:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[O:10][N:9]=1)=[O:2]
Reactant: Cn1ccnc1
Reactant: CCCCCCCCCCCCCCCCc1cc(OCC(COP(=O)([O-])OCCBr)Oc2ccon2)no1
Product: CCCCCCCCCCCCCCCCc1cc(OCC(COP(=O)([O-])OCC[n+]2ccn(C)c2)Oc2ccon2)no1

Procedure:
21(b) Following the procedure described in Example 17, 0.730 g of (2RS)-3-(5-hexadecyl-3-isoxazolyloxy)-2-(3-isoxazolyloxy)propyl 2-bromoethyl phosphate [prepared as described in step (a) above] was reacted with 0.91 ml of N-methylimidazole, to give 0.477 g of the title compound as a pale-yellow resinous material.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.Br[C:9]1[CH:14]=[CH:13][C:12]([C:15]([OH:24])([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=1.CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1>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].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1>[F:17][C:16]([F:18])([F:19])[C:15]([C:12]1[CH:11]=[CH:10][C:9]([N:6]2[CH2:5][CH2:4][NH:3][C@H:2]([CH3:1])[CH2:7]2)=[CH:14][CH:13]=1)([OH:24])[C:20]([F:21])([F:23])[F:22]
Reactant: C[C@@H]1CNCCN1
Reactant: OC(c1ccc(Br)cc1)(C(F)(F)F)C(F)(F)F
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CCN1
Temperature: 100 °C
Yield: 89.5 %

Procedure:
A 20 mL vial was charged with (R)-2-methylpiperazine (0.357 g, 3.56 mmol, Sigma-Aldrich, St. Louis, Mo.), 2-(4-bromophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (1.00 g, 3.10 mmol, Bioorg. Med. Chem. Lett. 2002, 12, 3009), sodium tert-butoxide (0.625 g, 6.50 mmol) and 6 mL of toluene. To this was added dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos) (0.022 g, 0.046 mmol, Strem Chemical Inc, Newburyport, Mass.), tris(dibenzylideneacetone)dipalladium (0) (0.014 g, 0.015 mmol, Strem Chemical Inc, Newburyport, Mass.). The vial was sealed in heated at 100° C. for 12 h. After that time, the mixture was diluted with water (20 mL) and extracted with EtOAc (2×50 mL). The combined extracts were dried (MgSO4) and concentrated to give 1,1,1,3,3,3-hexafluoro-2-(4-((3R)-3-methyl-1-piperazinyl)phenyl)-2-propanol (0.950 g) as an oil which was used without purification.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][C:31]=2[O:40][CH3:41])[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([S:12]([N:15](CC1C=CC(OC)=CC=1)[C:16]1[S:17][CH:18]=[CH:19][N:20]=1)(=[O:14])=[O:13])=[CH:7][CH:6]=2.C(Cl)Cl.C(O)(C(F)(F)F)=O>CO>[Cl:1][C:2]1[N:3]=[C:4]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:37])([F:38])[F:39])=[CH:32][C:31]=2[O:40][CH3:41])[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([S:12]([NH:15][C:16]1[S:17][CH:18]=[CH:19][N:20]=1)(=[O:14])=[O:13])=[CH:7][CH:6]=2
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4OC)nc(Cl)cc3c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COc1cc(C(F)(F)F)ccc1-c1nc(Cl)cc2cc(S(=O)(=O)Nc3nccs3)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A flask was charged with 3-chloro-1-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Intermediate RRR) (58.43 mg, 0.094 mmol), DCM (1 mL), and TFA (0.5 mL) to give a yellow solution (8:45 am). After 30 min of stirring at RT, the mixture was diluted with MeOH and concentrated. The residue was purified by chromatography on silica gel (0-10% MeOH/DCM) to give 47 mg of a light yellow solid. The solid was concentrated from DCM (2×), then taken up in DCM and filtered. The collected solid was washed with DCM (2×), then dried under vacuum for 10 min to give 3-chloro-1-(2-methoxy-4-(trifluoromethyl)phenyl)-n-(thiazol-2-yl)isoquinoline-6-sulfonamide as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm=12.95 (s, 1H), 8.57 (d, J=1.8 Hz, 1H), 8.39 (s, 1H), 7.87 (dd, J=1.8, 8.9 Hz, 1H), 7.72 (d, J=8.9 Hz, 1H), 7.61 (d, J=7.7 Hz, 1H), 7.56-7.48 (m, 2H), 7.30 (d, J=4.7 Hz, 1H), 6.90 (d, J=4.6 Hz, 1H), 3.76 (s, 3H). m/z (ESI) 500.2 (M+H)+.
Reaction SMILES: I[C:2]1[C:3](=[O:38])[NH:4][C:5](=[O:37])[N:6]([CH:36]=1)[C@@H:7]1[O:35][C@H:11]([CH2:12][O:13][C:14]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C@@H:9]([OH:10])[CH2:8]1.[Si:39]([C:43]#[CH:44])([CH3:42])([CH3:41])[CH3:40]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:40][Si:39]([C:43]#[C:44][C:2]1[C:3](=[O:38])[NH:4][C:5](=[O:37])[N:6]([CH:36]=1)[C@@H:7]1[O:35][C@H:11]([CH2:12][O:13][C:14]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C@@H:9]([OH:10])[CH2:8]1)([CH3:42])[CH3:41]
Reactant: C#C[Si](C)(C)C
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(I)c(=O)[nH]c3=O)C[C@@H]2O)(c2ccccc2)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C#C[Si](C)(C)C)c(=O)[nH]c3=O)C[C@@H]2O)(c2ccccc2)c2ccccc2)cc1

Procedure:
2 g of 2′-deoxy-5-iodo-5′-O-(4-methoxytrityl)-uridine (3.19 mmole) prepared in 1-1) together with (PPh3)2PdCl2 (0.1 eq) and 61 mg of CuI (0.1 eq), were dried under a vacuum, TEA and THF in a ratio of 3:1 were added thereto, and the mixture was purged several times with argon. 0.59 ml of TMS-acetylene (1.3 eq) was then added to the mixture at a temperature ranging from 45 to 50° C., until it became black. The resulting mixture was heated for additional 3 hours to terminate the reaction, and subjected to column chromatography (silica gel 60, 230˜400 meshes, Merck) to obtain the title compound as a pale yellow solid. The chromatography was conducted using a mixture of hexane and ethyl acetate as an elution solution whose mix ratio was gradually varied from 3:1 to 1:1 (v/v).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][C:8](=[O:14])[NH:9]2.[CH3:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19]Cl>>[CH3:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][N:1]([CH2:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:18]([CH3:19])[CH:17]=1)[CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][C:8](=[O:14])[NH:9]2
Reactant: Cc1cccc(CCl)c1
Reactant: NCCOc1cccc2c1CC(=O)N2
Product: Cc1cccc(CN(CCOc2cccc3c2CC(=O)N3)Cc2cccc(C)c2)c1
Yield: 34 %

Procedure:
Utilizing 4-(2-amino-ethoxy)-1,3-dihydro-indol-2-one prepared in example 2 and reacting with 3-methylbenzyl chloride in the same manner as described for intermediate 15 above to afford the title compound as a crystalline solid in 34% yield, mp 162-164.