Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[C:16]([F:17])=[CH:15][C:14]([F:18])=[CH:13][C:12]=2[CH:19]2[N:23]([CH2:24][CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:22](=[O:30])[C@H:21]([CH2:31][C:32](O)=[O:33])[S:20]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:35](Cl)[CH2:36]Cl.CCN(C(C)C)C(C)C.Cl.Cl.[NH:50]1[CH2:55][CH2:54][CH:53]([N:56]2[C:64]3C(=N[CH:61]=[CH:62][CH:63]=3)[NH:58][C:57]2=[O:65])[CH2:52][CH2:51]1>CN(C=O)C.CCOC(C)=O>[C:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[C:16]([F:17])=[CH:15][C:14]([F:18])=[CH:13][C:12]=2[CH:19]2[N:23]([CH2:24][CH2:25][C:26]([CH3:28])([CH3:27])[CH3:29])[C:22](=[O:30])[C@H:21]([CH2:31][C:32](=[O:33])[N:50]3[CH2:51][CH2:52][CH:53]([N:56]4[C:64]5[CH:63]=[CH:62][CH:61]=[CH:35][C:36]=5[NH:58][C:57]4=[O:65])[CH2:54][CH2:55]3)[S:20]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)CCN1C(=O)[C@H](CC(=O)O)SC1c1cc(F)cc(F)c1N1CCN(C(C)(C)C)CC1
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: ClCCCl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CCN1C(=O)[C@H](CC(=O)N2CCC(n3c(=O)[nH]c4ccccc43)CC2)SC1c1cc(F)cc(F)c1N1CCN(C(C)(C)C)CC1
Reaction time: 72 h
Yield: 15 %

Procedure:
2-((5S)-2-(2-(4-tert-Butylpiperazin-1-yl)-3,5-difluorophenyl)-3-(3,3-dimethylbutyl)-4-oxothiazolidin-5-yl)acetic acid (100 mg, 0.2 mmol), EDC (40 mg, 0.2 mmol), DIEA (52 mg, 0.4 mmol) and 1-(piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one bis HCl salt (60 mg, 0.2 mmol) were combined in DMF and let stir for 3 days. The mixture was then poured into EtOAc/sat'd NaHCO3. The organic layer was dried and concentrated to a solid and purified by reverse phase HPLC. Pure fractions were poured into EtOAc/1N NaOH and the organic layer was dried and concentrated to a solid, which was taken up in methanol. Then 4N HCl in dioxane was added. This solution was concentrated to give (5S)-2-(2-(4-tert-butylpiperazin-1-yl)-3,5-difluorophenyl)-3-(3,3-dimethylbutyl)-5-(2-oxo-2-(4-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-1-yl)ethyl)thiazolidin-4-one as a white solid (24 mg., 0.03 mmol, 15% yield). LC/MS MH+ 697.97.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]1([N:12]2[CH2:16][CH2:15][CH2:14][C@@H:13]2[C:17]([NH2:19])=O)[CH2:11][CH2:10][CH2:9][CH2:8]1.O>O1CCCC1.C(OCC)(=O)C>[NH3:12].[CH:7]1([N:12]2[CH2:16][CH2:15][CH2:14][C@@H:13]2[CH2:17][NH2:19])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: NC(=O)[C@H]1CCCN1C1CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: N
Product: NC[C@H]1CCCN1C1CCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 140.5 %

Procedure:
Lithium aluminum hydride (2.63 ml, 1M in tetrahydrofuran, 2.63 mmol) was added dropwise to a solution of (2R)-1-cyclopentyl-2-pyrrolidinecarboxamide (preparation 142) (320 mg, 1.76 mmol) in tetrahydrofuran (5 ml), and once addition was complete, the reaction was stirred at room temperature for 4 hrs. Water was added to quench the reaction, the mixture diluted with ethyl acetate and dried over MgSO4 This mixture was filtered through Whatman® fibre, and the filtrate evaporated under reduced pressure. The residue was purified by chromatography using a Biotage™ (KP-Sil™ 60 Å silica gel) cartridge and an elution gradient of dichloromethane:methanol:0.88 ammonia (95:5:0.5 to 90:10:1) to give the desired product as a clear oil, (208 mg, 71%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH:8]([CH2:11][CH:12]2[CH2:14][CH2:13]2)[C:9]#[N:10])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:20]([O:22][CH2:23][CH3:24])=[CH2:21])CCC>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:12]1([CH2:11][CH:8]([C:5]2[CH:6]=[N:7][C:2]([C:20]([O:22][CH2:23][CH3:24])=[CH2:21])=[CH:3][CH:4]=2)[C:9]#[N:10])[CH2:14][CH2:13]1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: N#CC(CC1CC1)c1ccc(Cl)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: C=C(OCC)c1ccc(C(C#N)CC2CC2)cn1
Temperature: 120 °C
Yield: 169.8 %

Procedure:
A solution of 2-(6-chloropyridin-3-yl)-3-cyclopropylpropanenitrile (1.0 g, 4.86 mmol), tributyl(1-ethoxyvinyl)stannane (3.4 g, 9.72 mmol), Lid (0.612 g, 14.58 mmol) and Pd(PPh3)4 (0.282 mg, 0.243 mmol) in 1,4-dioxane (20 mL) was degassed and heated to 120° C. under N2 overnight. The reaction mixture was diluted with water and extracted with EtOAc (3×30 mL). The combined organic layers were dried over Na2SO4 and concentrated to give 3-cyclopropyl-2-(6-(1-ethoxyvinyl)pyridin-3-yl)propanenitrile (2 g), which was used for the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:27][C:28]1[CH:29]=[N:30][C:31]2[C:36]([CH:37]=1)=[CH:35][CH:34]=[CH:33][CH:32]=2.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:10](=[O:12])[NH:27][C:28]1[CH:29]=[N:30][C:31]2[C:36]([CH:37]=1)=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:13][CH:14]1[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCN(C(=O)OC(C)(C)C)CC1)C(=O)O
Reactant: Nc1cnc2ccccc2c1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCN(C(=O)OC(C)(C)C)CC1)C(=O)Nc1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a solution of (2S)-2-{[(tert-butoxy)carbonyl]amino}-3-{1-[(tert-butoxy)carbonyl]piperidin-4-yl}propanoic acid LXXV (450 mg 1.21 mmol) and 3-aminoquinoline (187 mg, 1.30 mmol) in DCM (20 mL) was added DMT-MM (387 mg, 1.4 mmol). The mixture was stirred at r.t. overnight. The reaction was washed with water, 1 N HCl, satd. aq. NaHCO3, water and dried over Na2SO4. The product was purified on a silica gel column (1:1 EtOAc:hexane) to give tert-butyl 4-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-2-[(quinolin-3-yl)carbamoyl]ethyl]piperidine-1-carboxylate (425 mg, 0.85 mmol, 70% yield). 1H NMR (DMSO-d6) 1.02-1.10 (m, 2H), 1.40 (s, 18H), 1.54-1.73 (m, 9H), 4.22-4.25 (m, 1H), 7.20 (d, J=8 Hz, 1H), 7.55-7.66 (m, 2H), 7.94 (t, J=8 Hz, 2H), 8.69 (d, J=2 Hz, 1H), 8.93 (d, J=2 Hz, 1H), 10.44 (s, 1H). ESIMS found for C27H38N4O5 m/z 499 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][CH:11]=[C:12]([S:13](Cl)(=[O:15])=[O:14])[C:5]=2[O:4][C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH2:23]([CH2:25][NH2:26])[OH:24].C(N(CC)CC)C.O>O1CCCC1>[OH:24][CH2:23][CH2:25][NH:26][S:13]([C:12]1[C:5]2[O:4][C:3]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:2]([CH3:1])[C:7](=[O:8])[C:6]=2[CH:9]=[CH:10][CH:11]=1)(=[O:15])=[O:14]
Reactant: Cc1c(-c2ccccc2)oc2c(S(=O)(=O)Cl)cccc2c1=O
Reactant: NCCO
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccccc2)oc2c(S(=O)(=O)NCCO)cccc2c1=O

Procedure:
A solution of 5 g of Intermediate VIII in 37 ml of tetrahydrofuran was added dropwise at 0° C. to a mixture of 2.5 ml of ethanolamine and 2.5 ml of triethylamine in 25 ml of tetrahydrofuran. After stirring at 20°-25° C., the reaction mixture was poured into 400 ml of water. A precipitate formed, and was collected by suction filtration, washed with water and air dried, yielding 4.6 g of 8-(2-hydroxyethylsulfamyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran, melting at 186°-187° C. after crystallization from ethyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][CH2:11]2)=[CH:7][C:6]=1[NH2:14].[C:20](OC(=O)C)(=[O:22])[CH3:21].[C:27](O)(=[O:29])[CH3:28]>O.[O-2].[O-2].[O-2].[Cr+6]>[C:20]([NH:14][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][C:5]=1[O:4][C:3]1[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:2]=1[F:1])[C:11](=[O:29])[CH2:10][CH2:9]2)(=[O:22])[CH3:21].[C:27]([NH:14][C:6]1[CH:7]=[C:8]2[C:12]([CH2:11][CH2:10][C:9]2=[O:22])=[CH:13][C:5]=1[O:4][C:3]1[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:2]=1[F:1])(=[O:29])[CH3:28]
Reactant: CC(=O)O
Reactant: Nc1cc2c(cc1Oc1ccc(F)cc1F)CCC2
Reactant: CC(=O)OC(C)=O
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Product: CC(=O)Nc1cc2c(cc1Oc1ccc(F)cc1F)C(=O)CC2
Product: CC(=O)Nc1cc2c(cc1Oc1ccc(F)cc1F)CCC2=O
Reaction time: 0.67 h

Procedure:
13.9 g of 6-(2,4-difluorophenoxy)-5-indanylamine in 93 ml of acetic acid was combined at 30° C. with 40 ml of acetic anhydride. Thereafter a solution of 11 g of chromium trioxide in 27 ml of water and 17 ml of acetic acid was added dropwise at 50° C. After another 40 minutes at 50° C., the mixture was cooled, poured on ice water, and vacuum-filtered. The residue was chromatographed over silica gel with dichloromethane-ethyl acetate, thus obtaining 9 g of 5-acetylamino-6-(2,4-difluorophenoxy)-1-indanone, mp 153° C., and subsequently 4 g of the isomeric 6-acetylamino-5-(2,4-difluorophenoxy)-1-indanone, mp 199° C.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[C:27]([O:35][CH3:36])=[N:28][CH:29]=[C:30]([CH:32]([CH3:34])[CH3:33])[CH:31]=4)=[CH:24][N:23]=[C:22](S(C)(=O)=O)[N:21]=3)[C@H:14]2[CH3:41])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[F:45][C:46]1([F:50])[CH2:49][NH:48][CH2:47]1.C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C>[F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[C:27]([O:35][CH3:36])=[N:28][CH:29]=[C:30]([CH:32]([CH3:34])[CH3:33])[CH:31]=4)=[CH:24][N:23]=[C:22]([N:48]4[CH2:49][C:46]([F:50])([F:45])[CH2:47]4)[N:21]=3)[C@H:14]2[CH3:41])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: FC1(F)CNC1
Reactant: COc1ncc(C(C)C)cc1-c1cnc(S(C)(=O)=O)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ncc(C(C)C)cc1-c1cnc(N2CC(F)(F)C2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 60 °C
Reaction time: 8 h
Yield: 55.3 %

Procedure:
A solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5-(5-isopropyl-2-methoxypyridin-3-yl)-2-(methylsulfonyl)pyrimidin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (INTERMEDIATE 17, 80 mg, 0.126 mmol) in 1 mL THF was added to 1 dram vial that contained 3,3-difluoroazetidine hydrochloride (11.8 mg, 0.126 mmol). Triethylamine (0.071 mL, 0.506 mmol) was added, the vial was capped and the reaction mixture heated to 60° C. for 3 hours. The mixture was cooled to ambient temperature and stirred overnight. Diluted the mixture with ethyl acetate (2 mL) and washed with H2O (3×1 mL), brine (1×1 mL), dried over MgSO4, filtered and concentrated in vacuo. Purified the residue by RP HPLC (Waters Sunfire C18 column; 19×100 mm; 5 μM; CH3CN/H2O (0.1% TFA); 20-90% gradient; 20 mL/minutes; 12 minutes run) and the corresponding fractions that contained product were lyophilized to afford 45 mg of a white powder as the titled compound. LCMS (M+H)+: 646.3. 1H NMR (500 MHz, CDCl3): δ: 0.73 (d, 3H, J=7.5 Hz), 1.28 (d, 6H, J=6.9 Hz), 2.95 (septet, 1H, J=7.5 Hz), 3.95 (s, 3H), 4.04 (d, 1H, J=7.5 Hz), 4.54-4.59 (m, 4H), 4.64 (d, 1H, J=7.5 Hz), 5.65 (d, 1H, J=8.5 Hz), 7.40 (d, 1H, J=2.4 Hz), 7.73 (s, 2H), 7.90 (s, 1H), 8.13 (d, 1H, J=2.4 Hz), 8.23 (s, 1H). RTA IC50: 5 nM
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[C:5](Br)=[CH:4][C:3]=1[F:12].[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[ClH:1].[Cl:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[C:5]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:4][C:3]=1[F:12]
Reactant: C1CNCCN1
Reactant: Fc1cc(Br)c2occc2c1Cl
Product: Cl
Product: Fc1cc(N2CCNCC2)c2occc2c1Cl

Procedure:
Beginning with 4-chloro-5-fluoro-7-bromobenzofuran and piperazine, the title compound was prepared as described.
Reaction SMILES: [CH3:1][CH2:2][O:3][P:4]([O:19][CH2:20][CH3:21])([CH:6]([P:11]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:8][CH2:9]O)=[O:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:46]I>C(Cl)Cl>[CH3:1][CH2:2][O:3][P:4]([O:19][CH2:20][CH3:21])([CH:6]([P:11]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:8][CH2:9][I:46])=[O:5]
Reactant: CCOP(=O)(OCC)C(CCCO)P(=O)(OCC)OCC
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOP(=O)(OCC)C(CCCI)P(=O)(OCC)OCC
Reaction time: 2 h
Yield: 79.9 %

Procedure:
To a solution of 32 (1.52 g, 4.39 mmol) in CH2Cl2 (50 mL) were added triphenylphosphine (1.32 g, 5.033 mmol) and imidazole (0.45 g, 6.61 mmol). The reaction mixture was cooled to 0° C., before the addition of iodine (1.22 g, 4.81 mmol). The mixture was then removed from the cooling bath, stirred for 2 h, diluted with hexanes (100 mL) and filtered washing the precipitate with further hexanes (2×30 mL). The filtrate was evaporated and purified by flash chromatography on silica gel with gradient elution from 0-10% methanol/ethyl acetate to give pure 33 (1.6 g, 80%). 1H NMR (400 MHz, CDCl3) δ 1.32-1.38 (m, 12H), 1.95-2.15 (m, 4H), 2.28 (tt, J=24.1, 6.1, 1H), 3.18 (t, J=6.6, 2H), 4.12-4.24 (m, 8H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.Br[CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=[O:22]>>[CH:21]([C:20]1[CH:19]=[C:18]([CH:25]=[CH:24][CH:23]=1)[O:17][CH2:16][CH2:15][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1)=[O:22]
Reactant: O=Cc1cccc(OCCBr)c1
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Product: COC(=O)c1ccc2ccn(CCOc3cccc(C=O)c3)c2c1

Procedure:
Methyl 1H-indole-6-carboxylate was alkylated with 3-(2-bromoethoxy)benzaldehyde as described in Example 5, Step 1 to provide methyl 1-(2-(3-formylphenoxy)ethyl)-1H-indole-6-carboxylate.
Reaction SMILES: Cl.[CH2:2]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:17]1(=O)[CH2:21][CH2:20][CH2:19][CH2:18]1.[C-:23]#[N:24].[K+]>C(O)C.O>[C:11]1([CH2:10][N:9]([CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:17]2([C:23]#[N:24])[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: O=C1CCCC1
Reactant: [C-]#N
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CC1(N(Cc2ccccc2)Cc2ccccc2)CCCC1
Temperature: 0 °C

Procedure:
To an ice-cooled suspension of dibenzylamine hydrochloride (13.5 g; 0.058 mol) and cyclopentanone (4.86 g; 0.058 mol) in 25% ethanol in water (100 ml) was added ethanol (60 ml) and a solution of potassium cyanide (3.78 g; 0.058 mol) in water (35 ml) dropwise over 20 minutes with stirring. After 6 days the reaction mixture was extracted with ethyl acetate, washed with sodium bicarbonate solution, dried (Na2SO4) and evaporated in vacuo to afford the title compound as an off white solid (8.32 g, 49%). 1H NMR (CDCl3) δ: 1.72 (6H, m), 2.12 (2H, m), 3.78 (4H, m), 7.1-7.3 (10H, m); Mass Spectrum (Electrospray LC/MS): Found 264 (MH+−HCN). C20H22N2 requires 290. Ret. time 1.88 min.
Reaction SMILES: [I-].ClC1C=CC=C[N+]=1C.CCN(C(C)C)C(C)C.[NH2:19][C:20]1[S:21][C:22]([C:25]([NH:27][C:28]2[S:29][CH:30]=[C:31]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)[N:32]=2)=[O:26])=[CH:23][N:24]=1.[Br:40][C:41]1[S:42][C:43]([C:46](O)=[O:47])=[CH:44][N:45]=1>CN(C=O)C>[Br:40][C:41]1[S:42][C:43]([C:46]([NH:19][C:20]2[S:21][C:22]([C:25](=[O:26])[NH:27][C:28]3[S:29][CH:30]=[C:31]([C:33]4[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=4)[N:32]=3)=[CH:23][N:24]=2)=[O:47])=[CH:44][N:45]=1
Reactant: O=C(O)c1cnc(Br)s1
Reactant: Cc1ccc(-c2csc(NC(=O)c3cnc(N)s3)n2)cc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2csc(NC(=O)c3cnc(NC(=O)c4cnc(Br)s4)s3)n2)cc1
Temperature: 25 °C
Yield: 31.3 %

Procedure:
2-Chloro-1-methylpyridinium iodide (0.048 g, 0.18 mmol), DIEA (0.045 mL, 0.25 mmol) and 2-amino-N-(4-p-tolylthiazol-2-yl)thiazole-5-carboxamide (0.04 g, 0.126 mmol) were added to a solution of 2-bromothiazole-5-carboxylic acid (26 mg, 0.126 mmol) in DMF (1 mL). The resulting solution was stirred at RT until completion of the reaction. Then a solid was precipitated with AcOEt and the solid was separated by centrifugation, yielding 2-bromo-N-(5-(4-p-tolylthiazol-2-ylcarbamoyl)thiazol-2-yl)thiazole-5-carboxamide (20 mg, 30%) as a solid that was used in the following step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.[NH2:13][CH2:14][CH2:15][N:16]1[C:31](=[O:32])[C:30]([CH3:33])=[CH:29][N:18]([C@@H:19]2[O:25][C@H:22]([CH2:23][OH:24])[C@@H:21]([N:26]=[N+:27]=[N-:28])[CH2:20]2)[C:17]1=[O:34].CCN(CC)CC>CO>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([NH:13][CH2:14][CH2:15][N:16]2[C:31](=[O:32])[C:30]([CH3:33])=[CH:29][N:18]([C@@H:19]3[O:25][C@H:22]([CH2:23][OH:24])[C@@H:21]([N:26]=[N+:27]=[N-:28])[CH2:20]3)[C:17]2=[O:34])=[O:12])=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1ccc(O)cc1
Reactant: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)n(CCN)c1=O
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)n(CCNC(=O)CCc2ccc(O)cc2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 10 mg 3-(4-hydroxyphenyl)-propionic acid N-hydroxysuccinimideester (HPP:NOS) in MeOH was mixed with 10 mg of 3-AE-AZT (Example 27) dissolved in 100 ul MeOH. The mixture was stirred 30 minutes at room temperature, followed by addition of 2.5 ul of Et3N. This mixture was incubated overnight at room temperature, and then chromatographed by TLC on silica gel-F 250 um using the solvent system CHCl3 /MeOH/HOAc (90+10+1). The following Rf values were observed upon visualization by UV at 254 nm: 3-AE-AZT, 0.034;NOS, 0.28; product, 0.35; HPPA, 0.37; andHPP:NOS, 0.55. The product, unlike 3-(4-hydroxyphenyl)propionic acid (HPPA), was an effective inhibitor of polarization in a FPIA for AZT.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([OH:6])=[O:5].C[C@@H:8](O)[C@@H:9]1NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC2C=CC=CC=2)NC(=O)[C@H](CCN)NC(=O)[C@@H](NC([C@@H](N)CCN)=O)CC[NH:12][C:10]1=[O:11].OS(O)(=O)=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH3:106][C:107]([CH3:127])=[CH:108][CH2:109][CH2:110]/[C:111](/[CH3:126])=[CH:112]/[CH2:113][CH2:114]/[C:115](/[CH3:125])=[CH:116]/[CH2:117][S:118]C[C@H](N)C(O)=O>C(Cl)Cl>[C:10]([NH:12][C@@H:3]([CH2:2][S:118][CH2:117]/[CH:116]=[C:115](\[CH3:125])/[CH2:114][CH2:113]/[CH:112]=[C:111](\[CH3:126])/[CH2:110][CH2:109][CH:108]=[C:107]([CH3:106])[CH3:127])[C:4]([OH:6])=[O:5])(=[O:11])[CH:9]=[CH2:8]
Reactant: O=C(O)CCCl
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](N)C(=O)O
Reactant: CC(C)C[C@@H]1NC(=O)[C@@H](Cc2ccccc2)NC(=O)[C@H](CCN)NC(=O)[C@@H](NC(=O)[C@@H](N)CCN)CCNC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)N[C@@H](CSC/C=C(\C)CC/C=C(\C)CCC=C(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 100 mL round bottom flask, 3-chloro-propionic acid (1.0 mmol), coupling reagent (520 mg of PBOP or 380 mg of HATU, 1 mmol) and N,N-diisopropyl-ethyl-amine (650 mg, 5 mmol) were mixed in CH2Cl2 (10 mL). The reaction mixture was stirred at room temperature for 30 minutes. S-trans, trans-Farnesyl-L-cysteine (325 mg, 1 mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature overnight. CH2Cl2 was removed by rotary evaporation. The resulting residue was dissolved in ethyl acetate (50 mL). The organic solution was washed with an NH4Cl saturated solution (50 mL), dried over Na2SO4, and concentrated to afford a crude mixture. The crude mixture was purified by preparative HPLC (120 mg, 32%) to yield Compound N-42. 1H-NMR (500 MHz, CD3OD): δ 1.50 (s, 6H), 1.57 (s, 3H), 1.64 (s, 3H), 1.85-1.88 (m, 2H), 1.95-2.06 (m, 6H), 2.67 (dd, J=9.0, 14.0 Hz, 1H), 2.93 (dd, J=4.5, 14.0 Hz, 1H), 3.06 (dd, J=7.0, 13.0 Hz, 1H), 3.20 (dd, J=9.0, 14.0 Hz, 1H), 4.58 (dd, J=4.5, 8.5 Hz, 1H), 4.98-5.03 (m, 2H), 5.13 (t, J=7.5 Hz, 1H), 5.61 (d, J=10.0 Hz, 1H), 6.17 (d, J=17.0 Hz, 1H), 6.28 (dd, J=10.0, 17.0 Hz, 1H). 13C-NMR (125 MHz, CD3OD): δ 16.16, 16.25, 17.81, 25.96, 27.39, 27.79, 30.16, 33.36, 40.79, 40.89, 53.50, 121.60, 125.14, 125.47, 127.47, 131.65, 132.10, 136.27, 140.55, 168.00, 173.81; ES-MS: mass calcd for Chemical Formula: C21H33NO3S 379.56. Found (M+Na) m/z 402.2.
Reaction SMILES: N[C:2]1[C:6]2[CH:7]=[C:8]([C:11]3[CH:45]=[C:44]([Cl:46])[CH:43]=[CH:42][C:12]=3[O:13][C:14]3[C:19]([F:20])=[CH:18][C:17]([S:21]([N:24]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][C:32]=4[O:39][CH3:40])[C:25]4[S:29][N:28]=[CH:27][N:26]=4)(=[O:23])=[O:22])=[C:16]([F:41])[CH:15]=3)[CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.[CH2:47]=O.[C:49]([BH3-])#[N:50].[Na+]>C(O)(=O)C.C(OCC)(=O)C.[OH-].[Na+]>[Cl:46][C:44]1[CH:43]=[CH:42][C:12]([O:13][C:14]2[C:19]([F:20])=[CH:18][C:17]([S:21]([N:24]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][C:32]=3[O:39][CH3:40])[C:25]3[S:29][N:28]=[CH:27][N:26]=3)(=[O:22])=[O:23])=[C:16]([F:41])[CH:15]=2)=[C:11]([C:8]2[CH:9]=[CH:10][C:5]3[O:4][N:3]=[C:2]([N:50]([CH3:49])[CH3:47])[C:6]=3[CH:7]=2)[CH:45]=1
Reactant: [BH3-]C#N
Reactant: C=O
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(Oc3ccc(Cl)cc3-c3ccc4onc(N)c4c3)cc2F)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(Oc3ccc(Cl)cc3-c3ccc4onc(N(C)C)c4c3)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 35 %

Procedure:
To a mixture of 4-(2-(3-aminobenzo[d]isoxazol-5-yl)-4-chlorophenoxy)-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (0.686 g, 1.0 mmol) and paraformaldehyde (0.30 g, 10.0 mmol) in acetic acid (3 mL) was added sodium cyanoborohydride (0.19 g, 3.0 mmol) and the reaction mixture was stirred at ambient temperature for 16 h. The mixture was diluted with ethyl acetate (100 mL) and 1 M aqueous sodium hydroxide (10 mL) was added. The organic phase was washed with 1 M aqueous sodium hydroxide (10 mL) and brine (10 mL), dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was purified by column chromatography, eluting with a 25-100% gradient of ethyl acetate in hexanes to afford 4-(4-chloro-2-(3-(dimethylamino)benzo[d]isoxazol-5-yl)phenoxy)-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide as a beige solid 35% yield (0.25 g): MS (ES+) m/z 713.3 (M+1), 715.7 (M+1).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[CH:20][CH:19]=[CH:18]2>ClCCl>[CH3:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N+:21]([O-:9])=[CH:20][CH:19]=[CH:18]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cccc2cccnc12
Solvent: ClCCl
Product: Cc1cccc2ccc[n+]([O-])c12

Procedure:
A solution of 2.45 g of m-chloroperbenzoic acid in 15 ml of dichloromethane is added dropwise to a solution of 1 g of commercially available 8-methylquinoline in 15 ml of dichloromethane. The reaction mixture is stirred over night diluted with 30 ml of dichloremethane and extracted two times each with 50 ml of halfsaturated aqueous sodium hydrogencarbonate solution. The organic layer is dried over magnesium sulfate, filtered and evaporated in vacuo. The residue is chromatographed on silica gel (dichloromethane/methanol 98:2). 1 g of the title compound are obtained as colourless solid.