Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)=[CH:7][CH:6]=1)[NH2:4].CCN(C(C)C)C(C)C.[Br:28][CH2:29][CH2:30][CH2:31][C:32](Cl)=O>C(Cl)Cl>[Br:28][CH2:29][CH2:30][CH2:31][C:32]1[O:1][N:2]=[C:3]([C:5]2[CH:6]=[CH:7][C:8]([CH2:11][O:12][CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)=[CH:9][CH:10]=2)[N:4]=1
Reactant: NC(=NO)c1ccc(COC2CCCCO2)cc1
Reactant: O=C(Cl)CCCBr
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: BrCCCc1nc(-c2ccc(COC3CCCCO3)cc2)no1
Temperature: 0 °C
Reaction time: 8 h
Yield: 61.8 %

Procedure:
To a solution of N′-hydroxy-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]benzenecarboximidamide (Intermediate 27; 211 mg, 0.84 mmol) in DCM (3 mL) was added DIEA (0.176 mL, 1.01 mmol). The mixture was cooled to 0° C. and a solution of 4-bromobutanoyl chloride (0.108 mL, 0.88 mmol) in DCM (1 mL) was added dropwise. The mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure and the crude obtained was purified by column chromatography with silica gel, eluting with a mixture of Hexane:ether give the title compound as a solid (198 mg, 53%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]#[N:8])[N:2]=1.[ClH:9].[H][H]>CO.[Pd]>[ClH:9].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH2:8])[N:2]=1
Reactant: N#Cc1cccnn1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCc1cccnn1

Procedure:
To a solution of the intermediate from Step B (5.96 g, 56.7 mmol) in MeOH (35 mL) was added 6N HCl (20.89 mL, 125 mmol) followed by Pd/C (0.905 g, 8.51 mmol). The reaction mixture was kept on Parr shaker for 2 hours at 40 psig hydrogen. The reaction mixture was filtered through Celite™ (diatomaceous earth) and washed with 600 mL of MeOH and the filtrate concentrated. The residue was azeotroped several times with toluene. A dark brown solid was obtained. m/z=110 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[CH:6]=[N:5]2.[CH3:13][NH2:14]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:14][CH3:13])[CH:6]=[N:5]2
Reactant: CN
Reactant: Clc1cnc2cc(Br)ccc2n1
Solvent: C1CCOC1
Product: CNc1cnc2cc(Br)ccc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To solution of 6-bromo-2-chloro-quinoxaline (0.7 g, 1 eq, 2.87 mmol) in THF (6 mL) was added a solution of methyl amine in THF (3 mL) at room temperature. The mixture was stirred at room temperature for 2 h. After completion of the reaction, the volatiles were removed under vacuum and water (20 mL) was added to reaction mixture. The aqueous layer was extracted with ethyl acetate (15 mL×3). The organic layer was washed with water (20 mL) and brine (20 mL) and then dried over Na2SO4. The organic layer was concentrated under vacuum to afford the crude product.
Reaction SMILES: CS(O[CH:6]1[CH2:10][CH2:9][O:8][CH2:7]1)(=O)=O.[CH3:11][C:12]1([CH3:24])[C:16]([CH3:18])([CH3:17])[O:15][B:14]([C:19]2[CH:20]=[N:21][NH:22][CH:23]=2)[O:13]1.[H-].[Na+]>CN(C)C=O>[O:8]1[CH2:9][CH2:10][CH:6]([N:22]2[CH:23]=[C:19]([B:14]3[O:13][C:12]([CH3:24])([CH3:11])[C:16]([CH3:18])([CH3:17])[O:15]3)[CH:20]=[N:21]2)[CH2:7]1
Reactant: CS(=O)(=O)OC1CCOC1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OB(c2cnn(C3CCOC3)c2)OC1(C)C
Temperature: 60 °C

Procedure:
Tetrahydrofuran-3-yl methanesulfonate was dissolved in N,N-dimethylformamide (0.5 mL) and added to a pre-stirred solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (100 mg, 0.52 mmol) and sodium hydride (25 mg, 1.1 mmol) in N,N-dimethylformamide (1 mL). The mixture was heated to 60° C. for 2 d, cooled to RT, and purified by RP-HPLC to afford the desired product. LCMS: (M+H)=265.1.
Reaction SMILES: Cl[CH2:2][C:3]([O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([NH:13][C:14]2[CH:18]=[CH:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:15]=2)=[CH:8][C:7]=1[CH3:25])=[O:4].[C-:26]#[N:27].[Na+]>CS(C)=O>[C:26]([CH2:2][C:3]([O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([NH:13][C:14]2[CH:18]=[CH:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:15]=2)=[CH:8][C:7]=1[CH3:25])=[O:4])#[N:27]
Reactant: Cc1cc(Nc2ccn(-c3ccccc3)n2)cc(C)c1OC(=O)CCl
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(Nc2ccn(-c3ccccc3)n2)cc(C)c1OC(=O)CC#N

Procedure:
2,6-Dimethyl-4-(1-phenyl-1H-pyrazol-3-yl)aminophenyl chloroacetate, Example 4k, (1 g) and sodium cyanide (0.5 g) stirred in dimethyl sulfoxide for 16 hours gave, after dilution with brine, extraction with ethyl acetate and subsequent evaporation, the title compound (0.3 g), mp 116°-117° (from ethyl acetate/hexane).
Reaction SMILES: [Br:1][C:2]1[N:6]2[C:7](Br)=[CH:8][N:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH2:12]([NH2:14])[CH3:13].C1COCC1>C(Cl)Cl.O>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10]([NH:14][CH2:12][CH3:13])[C:5]2=[N:4][CH:3]=1
Reactant: Brc1cncc2ncc(Br)n12
Reactant: CCN
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CCNc1nccn2c(Br)cnc12
Temperature: 70 °C
Yield: 53 %

Procedure:
3,5-Dibromo-imidazo[1,2-a]pyrazine (D) (200 mg, 0.722 mol) was added to 2M ethylamine in THF (10.8 ml, 30 eq.). The mixture was heated at 70° C. in sealed tube for 8 hr. The mixture was then cooled to rt, and diluted with DCM (100 ml) and water (50 ml). The organic layer was washed with brine, dried and concentrated. The residue was purified on a silica gel column to give 92.2 mg (yield 53%) of (3-bromo-imidazo[1,2-a]pyrazin-8-yl)-ethyl-amine as a crystalline solid.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:11]([NH:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24])[CH:12]([CH3:14])[CH3:13].[N:26]#[C:27]Br>O1CCCC1>[C:27]([N:15]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24])#[N:26]
Reactant: N#CBr
Reactant: CC(C)CNc1cc(Cl)ccc1[N+](=O)[O-]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)CN(C#N)c1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
Add lithium bis(trimethylsilyl)amide (45 mL, 1M in tetrahydrofuran) to a solution of N-[isobutyl]2-nitro-5-chloroaniline (5.2 g, 0.0226 mol) in tetrahydrofuran (50 mL) cooled in an ice bathe Stir for 30 minutes and add cyanogen bromide (5.3 g, 0.050 mol). Stir at room temperature for 3 hours. Concentrate under reduced pressure. Dissolve residue in dichloromethane, wash saturated aqueous sodium chloride, dry over magnesium sulfate, filter, and concentrate under reduced pressure. Subject residue to silica gel chromatography, eluting with hexane/ethyl acetate mixtures to provide 5.26 g (0.021 mol) of desired compound.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:8]([C:17]([OH:19])=O)=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:24]=[C:25]([S:29]([NH2:32])(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN1C(=O)CCC1.CS(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[C:8]([C:17]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([S:29](=[O:31])(=[O:30])[NH2:32])[CH:24]=3)=[O:19])=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:20][CH:21]=1
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: O=C(O)c1nc2ccccc2nc1Oc1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CN1CCOCC1
Solvent: CN1CCCC1=O
Product: NS(=O)(=O)c1cccc(NC(=O)c2nc3ccccc3nc2Oc2ccc(F)cc2)c1
Yield: 31.7 %

Procedure:
A solution of 3-(4-fluorophenoxy)quinoxaline-2-carboxylic acid (28.42 mg, 0.1 mmol), 3-aminobenzenesulfonamide (20.7 mg, 0.12 mmol), HATU (38.0 mg, 0.10 mmol) and N-methylmorpholine (21.99 μL, 0.20 mmol) in NMP (0.5 mL) and DMSO (0.1 mL) was stirred at 25° C. for 16 hours. The reaction was filtered and purified by reverse phase HPLC using a gradient of 1-99% ACN in Water and HCl as a modifier. 3-(4-Fluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide (1) (13.9 mg, 32%) was obtained as a white solid. ESI-MS m/z calc. 438.08, found 439.5 (M+1)+; Retention time: 1.49 minutes (3 minutes run).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)=[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14][CH3:15])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10]Br.[CH3:29][NH2:30]>CO>[Br:1][C:2]1[CH:3]=[C:4]([C:12]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)=[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14][CH3:15])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][NH:30][CH3:29]
Reactant: CCC(=C(c1ccc(O)cc1)c1ccc(OCCBr)c(Br)c1)c1ccccc1
Reactant: CN
Solvent: CO
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCNC)c(Br)c1)c1ccccc1
Yield: 90 %

Procedure:
Following the same procedure as described in example 11, step D, 4-(1-(3-bromo-4-(2-bromoethoxy)phenyl)-2-phenylbut-1-enyl)phenol (0.09 g, 1.0 eq) was reacted with MeNH2 (30% wt in water, 10 mL) in MeOH (20 mL) under reflux to give 73 mg desired product (90% yield, Z/E=1/1). 1H NMR (400 MHz, CDCl3) δ 7.40 (s, 1H), 6.98-7.20 (m, 7H), 6.87 (d, J=8.4 Hz, 1H), 6.78 (d, J=8.4 Hz, 1H), 6.68 (d, J=8.8 Hz, 1H), 6.45 (d, J=8.4 Hz, 1H), 4.17 (t, J=5.2 Hz, 1H), 4.01 (t, J=4.8 Hz, 1H), 3.06 (t, J=4.8 Hz, 1H), 2.96 (t, J=5.2 Hz, 1H), 2.40-2.60 (m, 5H), 0.88 (t, J=5.2 Hz, 3H); m/z=452 [M+1]+.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([N:7]2[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)[N:3]=1.FC(F)(F)C(O)=O.[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[C:23]([NH:30][C:31]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[O:32])=[N:22]1.C(N(CC)CC)C.O>CN(C)C=O>[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[C:23]([NH:30][C:31]([N:33]2[CH2:38][CH2:37][N:36]([C:2]3[S:6][N:5]=[C:4]([N:7]4[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]4)[N:3]=3)[CH2:35][CH2:34]2)=[O:32])=[N:22]1
Reactant: O=C(Nc1noc2ccccc12)N1CCNCC1
Reactant: OC1CCN(c2nsc(Cl)n2)CC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1noc2ccccc12)N1CCN(c2nc(N3CCC(O)CC3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.1 %

Procedure:
To a solution of 1-(5-chloro-1,2,4-thiadiazol-3-yl)piperidin-4-ol (153 mg, 0.555 mmol) and N-1,2-benzisoxazol-3-ylpiperazine-1-carboxamide trifluoroacetate (200 mg, 0.555 mmol) in N,N-dimethylformamide (2 ml) was added triethylamine (0.387 ml, 2.78 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured to water, and a solid was separated by filtration and washed with water, which was recrystallized from a mixed solvent of tetrahydrofuran and ethyl acetate to give 79.0 mg (33.2%) of the desired product as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:33])=[C:6]([C:8]2[C:12]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([C@@H:24]4[CH2:29][CH2:28][CH2:27][CH2:26][NH:25]4)=[O:23])=[CH:17][CH:16]=3)=[CH:11][N:10]([CH2:30][CH2:31][OH:32])[N:9]=2)[CH:7]=1.[NH:34]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C@@H:35]([C:42](O)=[O:43])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.CC(C)N=C=NC(C)C>C1COCC1>[C:48]([O:47][C:45](=[O:46])[NH:34][C@H:35]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:42]([N:25]1[CH2:26][CH2:27][CH2:28][CH2:29][C@H:24]1[C:22](=[O:23])[NH:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]#[C:13][C:12]2[C:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[OH:33])=[N:9][N:10]([CH2:30][CH2:31][OH:32])[CH:11]=2)=[CH:20][CH:19]=1)=[O:43])([CH3:51])([CH3:49])[CH3:50]
Reactant: O=C(Nc1ccc(C#Cc2cn(CCO)nc2-c2cc(Cl)ccc2O)cc1)[C@@H]1CCCCN1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccccc1
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCCC[C@H]1C(=O)Nc1ccc(C#Cc2cn(CCO)nc2-c2cc(Cl)ccc2O)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
To a mixture of compound 10A (1.0 g, 2.15 mmol) and BOC-D-Phg-OH (11A, 0.65 g, 2.58 mmol) was added anhydrous THF (30 mL) and the resultant mixture was stirred at rt for 5 min. DIPC (0.40 mL, 2.58 mmol) was added slowly at rt. The final reaction mixture was stirred at rt overnight. The solvent was removed and the residua were dissolved in small amount of ethyl acetate. Solid was removed by filtration. The filtrate was purified by silica column chromatography eluting with hexanes-ethyl acetate (v/v 3/1, 2/1, 1/1 and 2/3). The product was recrystallized from hexanes-ethyl acetate gave the title compound (12A, 0.81 g) as white crystals in 54% yield. 1H NMR (CDCl3, 500 MHz) δ 10.60 (s, 1H), 8.70 (s, 1H), 8.49 (s, 1H), 7.81 (d, 2H, J=8.0 Hz), 7.77 (s, 1H), 7.55 (d, 2H, J=8.0 Hz), 7.41 (m, 5H), 7.20 (d, 1H, J=8.5 Hz), 6.96 (d, 1H, J=9.0 Hz), 5.58 (d, 1H, J=3.5 Hz), 5.53 (d, 2H, J=3.5 Hz), 4.31 (s, 2H), 4.06 (d, 2H, J=3.5 Hz), 3.86 (d, 1H, J=13.0 Hz), 3.16 (t, 1H, J=13.0 Hz), 2.48 (d, 1H, J=13.5 Hz), 2.00 (s, 1H), 1.61 (br s, 2H), 1.56-1.30 (m, 11H), 0.88 (m, 1H). LCMS (ESI) m/z 720.27 (MNa+), 698.22 (MH+), 642.10, 598.15, 345.16 (100), 289.14. HPLC: tR=5.25 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[O:11][N:10]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:8]=1[CH:17]=[CH2:18]>C(O)C.[Pd]>[CH2:17]([C:8]1[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:10][O:11][C:7]=1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[CH3:18]
Reactant: C=Cc1c(C(=O)OCC)noc1-c1ccccn1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1noc(-c2ccccn2)c1CC
Yield: 89.6 %

Procedure:
A solution of ethyl 5-(pyridin-2-yl)-4-vinylisoxazole-3-carboxylate (40 mg, 0.164 mmol) and Pd/C (3.49 mg, 0.033 mmol) in ethanol (3 mL) was placed on Parr Shaker under hydrogen (45 psi) for 5 h. Filtration to remove the catalyst followed by concentration under reduced pressure afforded ethyl 4-ethyl-5-(pyridin-2-yl)isoxazole-3-carboxylate (36.1 mg, 0.147 mmol, 90% yield). The compound had an HPLC retention time=3.13 min.—Column: YMC S5 COMBISCREEN® 4.6×50 mm; Gradient time: 4 min; Flow rate=4 ml/min; Solvent A=10% MeOH—90% Water—0.2% H3PO4; Solvent B=90% MeOH—10% water—0.2% H3PO4; Start % B=0; Final % B=100. LC-MS: M+1 247+. 1H NMR (400 MHz, MeOD) δ ppm 1.23 (t, 3H), 1.43 (t, J=7.15 Hz, 3H), 3.17 (q, J=7.53 Hz, 2H), 4.46 (q, J=7.28 Hz, 2H), 7.46 (ddd, J=7.03, 5.14, 1.63 Hz, 1H), 7.90-8.01 (m, 2H), and 8.73 (dt, J=4.77, 1.38 Hz, 1H).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-])=O)=[N:5][CH:4]=[C:3]1[C:17]([O:19][CH2:20][CH3:21])=[O:18].[H][H]>[Pd].C(O)C>[O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])=[N:5][CH:4]=[C:3]1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)c1cnc(-c2ccccc2[N+](=O)[O-])[nH]c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cnc(-c2ccccc2N)[nH]c1=O
Yield: 54.7 %

Procedure:
A mixture of ethyl 1,6-dihydro-6-oxo-2-(2-nitrophenyl)pyrimidine-5-carboxylate (0.91 g., 3.14 mmoles), 10% palladium on carbon (0.34 g.) and ethanol (200 ml.) was shaken in an atmosphere of hydrogen at an initial pressure of 3.5 kg./cm2. After hydrogen uptake ceased, the mixture was filtered and the filtrate concentrated. The residue was recrystallized from acetonitrile to give the title compound (0.445 g., 54.5%), m.p. 228°-230° (decomp.).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([S:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)[C:8]#[N:9].CC([Si](C)(C)[O:32][C:33]1[CH:42]=[C:41]2[C:36]([CH2:37][CH2:38][NH:39][CH2:40]2)=[CH:35][C:34]=1[O:43][CH3:44])(C)C.C(N)C>C(#N)C>[CH:21]1([S:20][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=2)([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:39]2[CH2:38][CH2:37][C:36]3[C:41](=[CH:42][C:33]([OH:32])=[C:34]([O:43][CH3:44])[CH:35]=3)[CH2:40]2)[C:8]#[N:9])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: COc1ccc(C(C#N)(CCCCCBr)SC2CCCCC2)cc1OC
Reactant: COc1cc2c(cc1O[Si](C)(C)C(C)(C)C)CNCC2
Agent: CCN
Solvent: CC#N
Product: COc1cc2c(cc1O)CN(CCCCCC(C#N)(SC1CCCCC1)c1ccc(OC)c(OC)c1)CC2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 150.7 %

Procedure:
A mixture, under argon, of 2.17 g of product from Example 113, 1.8 g of product from Example 28, 13.0 ml of N,N-diidopropyl ethylamine and 80 ml of acetonitrile is heated under reflux temperature for 8 hours. The reaction is cooled and concentrated in vacuo and dried under high vacuum for 1 hour. The crude residue is dissolved in 70 ml of tetrahydrofuran and 10.0 ml of 1M tetrabutyl ammonium fluoride in tetrahydrofuran is added and the mixture is stirred at room temperature, under argon, for 2.5 hours. The mixture is poured into water and extracted with ethyl acetate. The organic layer is washed with saturated sodium chloride, dried, filtered, and concentrated in vacuo to give 4.0 g of a brown oil. The oil is purified by chromatography (silica gel: 1%, 1.5% and 2% methyl alcohol/methylene chloride)to give 2.1 g of the desired product.
Reaction SMILES: [O:1]=[S:2]1(=[O:31])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:30])[N:14]([N:23]=[CH:24][C:25]3[O:26][CH:27]=[CH:28][CH:29]=3)[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[O:31]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:30])[N:14]([NH:23][CH2:24][C:25]3[O:26][CH:27]=[CH:28][CH:29]=3)[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1
Reactant: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc2n1N=Cc1ccco1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc2n1NCc1ccco1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 252A (0.058 g, 0.134 mmol) in tetrahydrofuran (3.0 mL) and methanol (0.010 mL, 0.268 mmol) at 0° C. was treated with dropwise addition of a 2.0M solution of lithium borohydride in tetrahydrofuran (0.105 mL, 0.210 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1 M hydrochloric acid to a pH of approximately 2-4, diluted with water (6.0 mL), and the resulting precipitate was collected by filtration and dried. The crude product was triturated with diethyl ether and filtered to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 4.03 (s, 2 H) 6.20 (t, J=6.07 Hz, 1 H) 6.35 (m, 1 H) 7.05 (t, J=7.72 Hz, 1 H) 7.29 (t, J=7.72 Hz, 3 H) 7.46 (t, J=7.72 Hz, 1 H) 7.56 (m, 2 H) 7.67 (d, J=7.72 Hz, 2 H) 8.06 (d, J=8.09 Hz, 1 H) 16.24 (s, 1 H). MS (ESI−) m/z 435 (M−H)−.
Reaction SMILES: O.[NH2:2][C@H:3]([C:8]([OH:10])=[O:9])[CH2:4][C:5](=[O:7])[NH2:6].C(=O)([O-])[O-].[K+].[K+].[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[C:17]([NH:2][C@H:3]([C:8]([OH:10])=[O:9])[CH2:4][C:5](=[O:7])[NH2:6])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NC(=O)C[C@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: NC(=O)C[C@H](NC(=O)c1ccccc1)C(=O)O
Reaction time: 2 h
Yield: 68.4 %

Procedure:
To a vigorously stirred solution of 2 g (0.013 mol) of L-asparagine monohydrate and 2.02 g (0.014 mol) of potassium carbonate in 15 ml of water, 1.51 ml (0.013 mol) of benzoyl chloride was added dropwise, over a period of 15 min., at room temperature. The stirring was continued for 2 hour, then the mixture was extracted with 10 ml of ether and the aqueous phase was acidified to pH 2 with concentrated hydrochloric acid. The white precipitate was filtered off, washed with water and purified by crystallization from isopropyl alcohol to give 2.1 g (68% yield) of the title compound at 190-192° C.; NMR (DMSO-d6): 2.62 (m, 2H, CH2); 3.32 (broad s, 1H, OH); 4.72 (m, 1H, CH); 6.64-8.0(m, 7H, aromatic, NH2); 8.6 (d, 1H, NH).
Reaction SMILES: COC1C=CC([NH:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)=CC=1.C(Br)CC>CC(C)=O>[CH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][C:14]=1[O:13][CH2:12][CH2:11][CH2:10][NH2:9]
Reactant: COc1ccc(NCCCOc2ccc3ccccc3c2)cc1
Solvent: CC(C)=O
Solvent: CCCBr
Product: NCCCOc1ccc2ccccc2c1

Procedure:
A mixture of N-(4-methoxyphenyl)-[3-(naphthalen-2-yloxy)propyl]amine (0.5 gm, 0.002 mole) and propyl bromide (0.54 ml, 0.003 mole) was taken in dry acetone (40 ml). It was refluxed for 12 hrs and the progress of reaction checked by TLC. Reaction mixture was filtered and the filtrate was concentrated to get oily compound which was further crystallized by benzene hexane mixture to get N-(4-methoxyphenyl)-N-propyl[3-(naphthalen-2-yloxy)propylamine, crystallized yellow solid, m.p. 127° C., (yield 0.67 gm, 95.7%)
Reaction SMILES: C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[CH2:20]([O:27][C:28]1[CH:29]=[CH:30][C:31]2[C:35]([O:36][C:37]3[CH:51]=[CH:50][C:40]([O:41][CH2:42][CH2:43][N:44]4[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]4)=[CH:39][CH:38]=3)=[C:34](Br)[S:33][C:32]=2[CH:53]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CC1(C)C(C)(C)OB([C:62]2[CH:67]=[CH:66][C:65]([S:68]([C:71]([F:74])([F:73])[F:72])(=[O:70])=[O:69])=[CH:64][CH:63]=2)O1.[F-].[Cs+]>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:20]([O:27][C:28]1[CH:29]=[CH:30][C:31]2[C:35]([O:36][C:37]3[CH:51]=[CH:50][C:40]([O:41][CH2:42][CH2:43][N:44]4[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]4)=[CH:39][CH:38]=3)=[C:34]([C:62]3[CH:63]=[CH:64][C:65]([S:68]([C:71]([F:73])([F:72])[F:74])(=[O:70])=[O:69])=[CH:66][CH:67]=3)[S:33][C:32]=2[CH:53]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Brc1sc2cc(OCc3ccccc3)ccc2c1Oc1ccc(OCCN2CCCCC2)cc1
Reactant: CC1(C)OB(c2ccc(S(=O)(=O)C(F)(F)F)cc2)OC1(C)C
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: CC#N
Product: O=S(=O)(c1ccc(-c2sc3cc(OCc4ccccc4)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)cc1)C(F)(F)F
Temperature: 90 °C
Yield: 55.3 %

Procedure:
Sonicate a suspension of palladium (II) acetate (146 mg, 0.65 mmol) and tricyclohexylphosphine (273 mg, 0.98 mmol) in acetonitrile (4 mL) for 10 minutes. In a separate flask, add a solution of 1-{2-[4-(6-benzyloxy-2-bromo-benzo[b]thiophen-3-yloxy)-phenoxy]-ethyl}-piperidine (350 mg, 0.65 mmol) and 4,4,5,5-tetramethyl-2-(4-trifluoromethanesulfonyl-phenyl)-[1,3,2]dioxaborolane (531 mg, 2.0 mmol) in acetonitrile (9 mL) to cesium fluoride (889 mg, 5.9 mmol). Add the sonicated catalyst mixture, and heat to 90° C. for 2 hours. Concentrate in vacuo and partition the residue between ethyl acetate (20 mL) and saturated aqueous sodium bicarbonate (20 mL). Combine the organic layer with saturated aqueous ammonium chloride (20 mL) and filter. Wash the organic layer with brine (20 mL), dry with sodium sulfate, and concentrate in vacuo. Chromatbgraph the residue on a SiO2 column eluting with methanol in dichloromethane (0 to 3%) to give 240 mg of the title compound (55%) contaminated with tricyclohexylphosphine oxide. 1H NMR (CDCl3): δ 8.03-7.95 (m, 4H), 7.45-7.33 (m, 5H), 7.32 (d, J=2.3 Hz, 1H), 7.29 (d, J=8.9 Hz, 1H), 6.96 (dd, J=9.0, 2.2 Hz, 1H), 6.89-6.79 (m, 4H), 5.13 (s, 2H), 4.03 (t, J=6.0 Hz, 2H), 2.73 (t, J=6.0 Hz, 2H), 2.48 (bs, 4H), 1.96-1.18 (complex multiplet obscured by P(O)Cy3, 6H).
Reaction SMILES: C([O:5][C:6](=[O:31])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][C:19]3[N:20]=[C:21]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[S:22][C:23]=3[CH3:24])[CH:15]=2)[CH:10]=[CH:9]1)(C)(C)C.[Li+].[OH-]>>[CH3:24][C:23]1[S:22][C:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:20][C:19]=1[CH2:18][O:17][C:14]1[CH:15]=[C:16]2[C:11]([CH:10]=[CH:9][N:8]2[CH2:7][C:6]([OH:31])=[O:5])=[CH:12][CH:13]=1
Reactant: Cc1sc(-c2ccccc2)nc1COc1ccc2ccn(CC(=O)OC(C)(C)C)c2c1
Agent: [Li+]
Agent: [OH-]
Product: Cc1sc(-c2ccccc2)nc1COc1ccc2ccn(CC(=O)O)c2c1

Procedure:
In analogy to the procedure described in example 2 c], [6-(5-methyl-2-phenyl-thiazol-4-ylmethoxy)-indol-1-yl]-acetic acid tert-butyl ester was treated with LiOH to obtain [6-(5-methyl-2-phenyl-thiazol-4-ylmethoxy)-indol-1-yl]-acetic acid as light yellow foam.