Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][C:10]1[S:14][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][C:11]=1[C:19]1[N:23]([CH3:24])[N:22]=[CH:21][CH:20]=1>O1CCCC1>[Br:8][C:20]1[CH:21]=[N:22][N:23]([CH3:24])[C:19]=1[C:11]1[CH:12]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[S:14][C:10]=1[CH3:9]
Reactant: COC(=O)c1cc(-c2ccnn2C)c(C)s1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: COC(=O)c1cc(-c2c(Br)cnn2C)c(C)s1
Temperature: 70 °C
Yield: 91.7 %

Procedure:
NBS (2.03 g, 11.41 mmol) was added in portions to a 75 mL sealed tube reactor containing methyl 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (2.1 g, 8.89 mmol) [prepared according to the procedure of Preparation 10] in Tetrahydrofuran (THF) (40 ml) at room temperature. The mixture was heated to 70° C. for 1 hour. The reaction mixture was partitioned between CHCl3 and H2O, the organic layer dried with Na2SO4, the reaction mixture adsorbed onto silica and purified via column chromatography (15-40% EtOAc/Hex) affording the title compound (2.57 g, 8.15 mmol, 92%): LC-MS (ES) m/z=316 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)=[N:9][CH:10]=[C:4]2[CH:3]=1.C([Li])CCC.[CH3:23][C:24]1([CH3:45])[O:28][CH:27]([CH2:29][N:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]([C:39](=[O:44])[C:40]([F:43])([F:42])[F:41])=[CH:31]2)[CH2:26][O:25]1>C1COCC1>[CH3:23][C:24]1([CH3:45])[O:28][CH:27]([CH2:29][N:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]([C:39]([C:2]3[CH:7]=[CH:6][N:5]4[C:8]([C:11]5[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=5)=[N:9][CH:10]=[C:4]4[CH:3]=3)([OH:44])[C:40]([F:43])([F:42])[F:41])=[CH:31]2)[CH2:26][O:25]1
Reactant: Fc1ccc(-c2ncc3cc(Br)ccn23)cc1
Reactant: CC1(C)OCC(Cn2cc(C(=O)C(F)(F)F)c3ccccc32)O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)OCC(Cn2cc(C(O)(c3ccn4c(-c5ccc(F)cc5)ncc4c3)C(F)(F)F)c3ccccc32)O1
Reaction time: 0.03 h
Yield: 33.7 %

Procedure:
To a chilled (−78° C.) solution of 7-bromo-3-(4-fluorophenyl)imidazo[1,5-a]pyridine (160 mg, 0.55 mmol) in anhydrous THF (3 mL) was added n-butyllithium (275 μL of a 2.5 M solution in hexanes, 0.69 mmol). After 2 minutes, a chilled (−78° C.) solution of 1-[1-(2,2-dimethyl-1,3-dioxolan-4-ylmethyl)-1H-indol-3-yl]-2,2,2-trifluoroethanone (240 mg, 0.73 mmol) in 1 mL of THF was added. After 60 minutes, the mixture was quenched with brine (50 mL) and extracted with ethyl acetate. The combined organic layers were washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo to afford a yellow oil. The residue was purified by column chromatography over silica gel eluting with 0-75% ethyl acetate in hexanes and fractions corresponding to a MS m/z 540 (MH+) peak were pooled and concentrated in vacuo to afford 100 mg of the title compound as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[CH:4][C:3]=1C.[CH3:13][O:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[S:25])=[C:19]([CH3:26])[CH:18]=1)=[O:16].OCCN.O=S(Cl)Cl>>[OH:8][CH2:6][C:5]1([NH2:23])[CH2:4][CH2:2][CH2:11][CH2:10]1.[CH3:13][O:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]2[S:25][CH2:11][C:2]3([CH2:3][CH2:4][CH2:5][CH2:10]3)[NH:1]2)=[C:19]([CH3:26])[CH:18]=1)=[O:16]
Reactant: COC(=O)c1ccc(N=C=S)c(C)c1
Reactant: COC(=O)c1ccc(N)c(C)c1
Solvent: O=S(Cl)Cl
Solvent: NCCO
Product: COC(=O)c1ccc(N=C2NC3(CCCC3)CS2)c(C)c1
Product: NC1(CO)CCCC1

Procedure:
Methyl 4-amino-3-methylbenzoate was converted to 4-methoxycarbonyl-2-methylphenyl isothiocyanate according to Method A2b. 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was sequentially reacted with SOCl2 and 4-methoxycarbonyl-2-methylphenyl isothiocyanate according to Method C2a to give 2-(4-methoxycarbonyl-2-methylphenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2h to give 2-(4-methoxycarbonyl-2-methylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: Cl[CH:2]([CH3:4])[CH3:3].[CH3:5][NH:6][C:7](=[O:25])/[C:8](/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[N:9]/[O:10][CH3:11]>>[CH3:5][NH:6][C:7](=[O:25])/[C:8](/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][C:19]1[CH:20]=[CH:21][C:22]([CH:2]([CH3:4])[CH3:3])=[CH:23][CH:24]=1)=[N:9]/[O:10][CH3:11]
Reactant: CC(C)Cl
Reactant: CNC(=O)/C(=N/OC)c1ccccc1Oc1ccccc1
Product: CNC(=O)/C(=N/OC)c1ccccc1Oc1ccc(C(C)C)cc1

Procedure:
In the same manner as in Example 14, the objective compound was prepared from 2-chloropropane and (E)-N-methyl-2-(2-phenoxyphenyl) -2-methoxyiminoacetamide.
Reaction SMILES: [C:1]1([C:7]2[NH:11][N:10]=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]([O:16][C:17]([N:19]1[CH2:23][CH:22](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:21][CH:20]1[C:35](N1CCN(C2C=CC=CC=2C#N)CC1)=[O:36])=[O:18])([CH3:15])([CH3:14])[CH3:13].[C:51](=O)([O-])[O-:52].[Na+].[Na+]>CN(C=O)C.CC(=O)OCC>[CH3:51][O:52][C:35]([CH:20]1[CH2:21][CH:22]([N:9]2[N:10]=[N:11][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8]2)[CH2:23][N:19]1[C:17]([O:16][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:18])=[O:36]
Reactant: O=C([O-])[O-]
Reactant: c1ccc(-c2nnn[nH]2)cc1
Reactant: Cc1ccc(S(=O)(=O)OC2CC(C(=O)N3CCN(c4ccccc4C#N)CC3)N(C(=O)OC(C)(C)C)C2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C1CC(n2nnc(-c3ccccc3)n2)CN1C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
To a solution of a corresponding phenyl-tetrazole in DMF is added 2-[4-(2-cyano-phenyl)-piperazine-1-carbonyl]-4-(toluene-4-sulfonyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester and anhydrous sodium carbonate. The mixture is stirred at about 60 degree overnight. The solution is diluted with EA, washed, dried and concentrated to give the corresponding 4-[5-(phenyl)-tetrazol-2-yl]-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (4).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][S:8]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1)(=[O:10])=[O:9].[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1.[C:30](=[O:33])([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]([CH2:15][C:14]1[CH:18]=[CH:19][C:11]([O:33][CH3:30])=[CH:12][CH:13]=1)[S:8]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([O:17][CH2:26][C:25]2[CH:28]=[CH:29][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)=[O:16])=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: COc1ccc(CCl)cc1
Reactant: O=C(O)c1ccc(S(=O)(=O)NCc2ccco2)cc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)c2ccc(S(=O)(=O)N(Cc3ccc(OC)cc3)Cc3ccco3)cc2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 160.4 %

Procedure:
4-(N-(furan-2-ylmethyl)sulfamoyl)benzoic acid (Example 5-2b) (500 mg, 1.8 mmol), p-methoxy benzyl chloride (624 mg, 4.0 mmol), and cesium carbonate (1.3 g, 4.0 mmol) were dissolved in DMF (10 mL) and stirred at 80° C. for 1 hour. The mixture was cooled to ambient temperature, diluted with H2O (200 mL), and extracted with ethyl acetate (3×100 mL). The combined organics were dried over sodium sulfate and concentrated on the rotovap. The product was purified by silica gel chromatography (15% ethyl acetate in hexanes) to provide the 4-methoxybenzyl 4-(N-(furan-2-ylmethyl)-N-(4-methoxybenzyl)sulfamoyl)benzoate (753 mg, 80%) as a clear oil. 1H NMR (DMSO-d6, 400 MHz): δ 3.70 (s, 3H), 3.75 (s, 3H), 4.22 (s, 2H), 4.26 (s, 2H), 5.39 (s, 2H), 6.14 (d, 1H, J=3.2 Hz), 6.25 (m, 1H), 6.87 (d, 2H, J=8.8 Hz), 6.97 (d, 2H, J=8.8 Hz), 7.13 (d, 2H, J=8.4 Hz), 7.39 (m, 1H), 7.43 (d, 2H, J=8.4 Hz), 7.91 (d, 2H, J=8.4 Hz), 8.07 (d, 2H, J=8.4 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.C([Li])CCC.[I:14]I.[O-]S([O-])(=S)=O.[Na+].[Na+]>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[I:14]
Reactant: Fc1cccc(F)c1
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Fc1cccc(F)c1I
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
(Roe, A. M.; Burton, R. A.; Willey, G. L.; Baines, M. W.; Rasmussen, A. C. J. Med. Chem. 1968, 11, 814–819. Tamborski, C.; Soloski, E. J. Org. Chem. 1966, 31, 746–749. Grunewald, G. L.; Arrington, H. S.; Bartlett, W. J.; Reitz, T. J.; Sall, D. J. J. Med. Chem. 1986, 29, 1972–1982.) 1,3-Difluorobenzene (57.05 g, 0.5 M) in THF (75 mL) was added to a −78° C. stirred solution of n-butyllithium (n-BuLi) (200 mL, 2.5 M/hexanes, 0.5 M) and THF (500 mL) under N2. By controlling the addition rate the internal temperature was maintained below −70° C. The total addition time was ˜½ hour. The resulting slurry was stirred an additional ½ hour, then the dispersion was treated with a solution of iodine (126.9 g, 0.5 M) in THF (300 mL) at a rate that maintained an internal temperature below −70° C. After complete addition the mixture was allowed to warm to room temperature, and was treated with H2O (100 mL) and 10% aqueous Na2S2O3 solution (100 mL) and stirred. The layers were separated and the aqueous layer extracted with hexanes (2×250 mL). The combined organic layer was washed with 10% aqueous Na2S2O3 solution (100 mL), H2O (100 mL), saturated aqueous NaCl solution (100 mL), dried (Na2SO4) filtered and concentrated to give a yellow oil (106.5 g). Distillation at ˜1–5 mm at ˜80° C. provided a light yellow oil (89.5 g, 75%). 1H NMR (400 MHz, CDCl3) δ 7.30 (m, 1H), 6.87 (m, 2H). GCMS m/e 240 (M+).
Reaction SMILES: [C:1]([O:4][CH:5](Br)[CH3:6])(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[F:14][C:15]1[C:25]([NH:26][CH2:27][C:28]2[CH:33]=[C:32]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=3)[CH:31]=[CH:30][C:29]=2[F:41])=[C:24]([F:42])[CH:23]=[CH:22][C:16]=1[O:17][CH2:18][C:19]([OH:21])=[O:20]>CC(N(C)C)=O>[F:14][C:15]1[C:25]([NH:26][CH2:27][C:28]2[CH:33]=[C:32]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=3)[CH:31]=[CH:30][C:29]=2[F:41])=[C:24]([F:42])[CH:23]=[CH:22][C:16]=1[O:17][CH2:18][C:19]([O:21][CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH3:6])=[O:20]
Reactant: O=C(O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F
Reactant: CC(=O)OC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(=O)OC(C)OC(=O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F
Temperature: 30 °C
Reaction time: 1.5 h
Yield: 23.9 %

Procedure:
1-bromoethyl acetate (700 mg, 1.7 mmol, 1.0 eq) was dissolved in DMA (10 mL) at room temperature. K2CO3 (120 mg, 0.9 mmol, 0.5 mmol) was added and the mixture stirred for 90 min at 30° C. under a nitrogen atmosphere. The reaction was cooled to −5° C. and 2-[2,4-difluoro-3-[[2-fluoro-5-(3-fluorophenyl)phenyl]methylamino]phenoxy]acetic acid (I(b)) (350 mg, 2.1 mmol, 1.2 eq) was added. The reaction was warmed to 30° C. over 30 min and stirred for a further 30 min. The reaction was quenched by addition of water and extracted with ethyl acetate. The organic extract was dried (Na2SO4), filtered and evaporated in vacuo and the residue obtained purified by column chromatography (petroleum ether: EtOAc, 10:1) to give the title compound as a colourless oil (200 mg, 23%).
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)=[O:4].[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[C:18]([O:20][C@@H:21]2[CH:26]3[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]3)[CH2:22]2)=[O:19])=[CH:13][CH:12]=1.CCOCC>CCOC(C)=O>[Cl-:1].[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([N:29]2[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]2)[C:18]([O:20][C@@H:21]2[CH:26]3[CH2:27][CH2:28][N+:23]([CH2:2][C:3](=[O:4])[C:5]4[S:6][CH:7]=[CH:8][CH:9]=4)([CH2:24][CH2:25]3)[CH2:22]2)=[O:19])=[CH:13][CH:12]=1
Reactant: O=C(CCl)c1cccs1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(c1ccc(F)cc1)N1CCCCC1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C(c1ccc(F)cc1)N1CCCCC1)C2)c1cccs1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 26.7 %

Procedure:
2-Chloro-1-(thiophen-2-yl)ethanone (30.6 mg, 0.19 mmol) was added to a solution of (R)-quinuclidin-3-yl 2-(4-fluorophenyl)-2-(piperidin-1-yl)acetate (60 mg, 0.17 mmol) in EtOAc (3 ml). The reaction was stirred at room temperature for 16 hours. Et2O was added the precipitate was collected by filtration and purified by flash chromatography (DCM/MeOH/NH4OH=97/3/0.3) to obtain (3R)-3-(2-(4-fluorophenyl)-2-(piperidin-1-yl)acetoxy)-1-(2-oxo-2-(thiophen-2-yl)ethyl)-1-azoniabicyclo[2.2.2]octane chloride (23 mg, 26.2% yield) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15](=[O:17])[CH3:16])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:33]1([CH2:39][CH2:40][S:41][CH:42]([C:46](O)=[O:47])[C:43](O)=[O:44])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1>[OH:47][C:46]1[CH:16]=[C:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:10]=2)[O:17][C:43](=[O:44])[C:42]=1[S:41][CH2:40][CH2:39][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Reactant: CC(=O)c1cccc(OCc2ccccc2)c1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1oc(-c2cccc(OCc3ccccc3)c2)cc(O)c1SCCc1ccccc1

Procedure:
The title compound was prepared by Method A using 3'-benzyloxyacetophenone (1.14 g, 5.06 mmol), lithium bis(trimethylsilyl) amide (0.930 g, 5.56 mmol), chlorotrimethylsilane (0.705 mL, 5.56 mmol), THF (57 mL), and diethyl ester of [(2-phenylethyl)thio]propanedioic acid (1.00 g, 3.37 mmol). m.p. 126°-127° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.78 (t, 2 H), 3.01 (t, 2 H), 5.20 (s, 2 H), 6.81 (s, 1 H), 7.22 (m, 6 H), 7.41 (m, 7 H).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH2:10]([N:12]1[C:16]([O:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=2)=[CH:15][C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([NH:36][S:37]([CH2:40][C:41]([F:44])([F:43])[F:42])(=[O:39])=[O:38])([CH3:35])[CH3:34])[CH:28]=2)=[N:13]1)[CH3:11].[C:45]([NH:48][NH2:49])(=[O:47])[CH3:46]>CN(C=O)C>[C:45]([NH:48][NH:49][C:22]([C:21]1[CH:25]=[CH:26][C:18]([O:17][C:16]2[N:12]([CH2:10][CH3:11])[N:13]=[C:14]([C:27]3[CH:28]=[C:29]([C:33]([NH:36][S:37]([CH2:40][C:41]([F:42])([F:44])[F:43])(=[O:39])=[O:38])([CH3:34])[CH3:35])[CH:30]=[CH:31][CH:32]=3)[CH:15]=2)=[CH:19][CH:20]=1)=[O:24])(=[O:47])[CH3:46]
Reactant: CC(=O)NN
Reactant: CCn1nc(-c2cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c2)cc1Oc1ccc(C(=O)O)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCn1nc(-c2cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c2)cc1Oc1ccc(C(=O)NNC(C)=O)cc1
Temperature: 22 °C
Reaction time: 16 h
Yield: 35 %

Procedure:
(1-benzotriazol-1-yloxy)[tris(dimethylamino)]phosphonium hexafluorophosphate (161 mg, 0.36 mmol, 1.2 equiv) and diisopropylethylamine (117 mg, 0.91 mmol, 3 equiv) were added to a stirring solution of 4-({1-ethyl-3-[3-(2-{[(2,2,2-trifluoroethyl)sulfonyl]amino}propan-2-yl)phenyl]-1H-pyrazol-5-yl}oxy)benzoic acid (155 mg, 0.30 mmol, 1 equiv) in DMF (3 mL). Acetohydrazide (45 mg, 0.61 mmol, 2 equiv) was then added and the mixture was stirred at 22° C. for 16 hours. The mixture was purified directly by reversed phase HPLC (0-95% acetonitrile:water with 0.025% TFA). Pure fractions were identified, combined, and lyophilized to give N-{2-[3-(5-{4-[(2-acetylhydrazinyl)carbonyl]phenoxy}-1-ethyl-1H-pyrazol-3-yl)phenyl]propan-2-yl}-2,2,2-trifluoroethanesulfonamide (35% yield). This material was stirred in THF (1 mL) at 22° C. and 3,3,3-triethyl-1-(methoxycarbonyl)diazathian-3-ium-1-ide 2,2-dioxide (38 mg, 0.16 mmol, 1.5 equiv) was added. The resulting mixture was stirred at 22° C. for 16 hours then purified directly by reversed phase HPLC (0-95% acetonitrile:water with 0.025% TFA). Pure fractions were identified, combined, and lyophilized to give the title compound (21% yield). Calc'd (M+1)+: 550.2. Found: 550.1.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]2[N:6]=[C:7]([NH:9][C:10]3[CH:30]=[CH:29][C:13]([C:14]([NH:16][NH:17][C:18]4C=[CH:27][CH:26]=[CH:25][C:19]=4[C:20]([O:22][CH2:23][CH3:24])=[O:21])=O)=[CH:12][CH:11]=3)[S:8][C:4]=2[CH:3]=1.C(Cl)(Cl)(Cl)Cl.C([N:41](C(C)C)CC)(C)C.C(P(CC)CC)C>C(Cl)Cl.C1COCC1>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]2[N:6]=[C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([C:14]4[N:41]5[CH:27]=[CH:26][CH:25]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:18]5=[N:17][N:16]=4)=[CH:29][CH:30]=3)[S:8][C:4]=2[CH:3]=1
Reactant: CCOC(=O)c1ccccc1NNC(=O)c1ccc(Nc2nc3ccc(Cl)cc3s2)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: CCP(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)c1cccn2c(-c3ccc(Nc4nc5ccc(Cl)cc5s4)cc3)nnc12
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 80 %

Procedure:
To a solution of ethyl 2-(2-(4-(6-chlorobenzo[d]thiazol-2-ylamino)benzoyl)hydrazinyl)benzoate (142 mg, 0.3 mmol) in a mixed solvent of CCl4 (0.6 mL), THF (0.8 mL) and CH2Cl2 (1.2 mL) cooled to 0° C. was added diisopropylethylamine (392 mg, 3 mmol) under argon atmosphere and then triethylphosphine (179 mg, 1.52 mmol). The mixture was stirred at 0° C. for 45 min, and then quenched with water (2.5 mL). The resulting precipitate was isolated by filtration and air dried to yield the title compound as a brown solid (108 mg). The filtrate was concentrated in vacuo to yield additional product (15 mg) (total 123 mg, 90% yield). HPLC/MS (Method C): retention time=2.21 min, [M+H]+=450.3.
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=12.Cl[CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][N:19]=[C:18]2[NH:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1.C(Cl)Cl>CN(C=O)C>[N:1]1[N:2]=[CH:3][N:4]2[CH2:9][CH2:8][N:7]([CH2:11][CH2:12][CH2:13][O:14][C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][C:24]=3[O:25][CH3:26])[N:21]=[CH:20][N:19]=[C:18]4[NH:27][C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[CH2:6][C:5]=12
Reactant: c1nnc2n1CCNC2
Reactant: COc1cc2ncnc(Nc3ccc(F)cc3)c2cc1OCCCCl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3ccc(F)cc3)c2cc1OCCCN1CCn2cnnc2C1
Temperature: 80 °C
Yield: 22.1 %

Procedure:
To a solution of 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (0.16 g) in DMF (8 mL) was added Ag2CO3 (0.98 g) and a solution of 6-(3-chloropropoxy)-N-(4-fluorophenyl)-7-methoxyquinazolin-4-amine (0.32 g) in DMF (2 mL) at room temperature under stirring. The mixture was heated at 80° C. for 36 h under N2, and cooled to room temperature. To this, CH2Cl2 (100 mL) was added. The mixture was washed with brine (100 mL×3). The organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 20:1 (v/v) CH2Cl2/CH3OH) to give the title compound as a white solid (87.70 mg, 20.41%), HPLC: 90.53%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 450.2 (M+1); 1H NMR (400 MHz, CDCl3) δ: 2.02-2.10 (m, 2H), 2.68 (t, J=13.20 Hz, 2H), 3.03 (t, J=10.80 Hz, 2H), 3.75 (s, 2H), 3.89 (s, 3H), 4.03 (t, J=10.80 Hz, 2H), 4.08 (t, J=12.40 Hz, 2H), 7.12 (m, 1H), 7.26 (s, 1H), 7.29 (t, J=6.00 Hz, 1H), 7.38 (s, 1H), 7.54-7.58 (m, 2H), 7.81-7.84 (m, 1H), 8.07 (s, 1H), 8.46 (s, 1H), 8.70 (s, 1H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:17]O)[CH:15]=3)[N:10]([C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.CS([Cl:49])(=O)=O.C(OCC)(=O)C>C(Cl)Cl>[Cl:49][CH2:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:19]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[N:9]=[C:8]2[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: OCc1ccc2c(c1)c(-c1cccc(F)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Fc1cccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(CCl)cc23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under ice-cooling, a solution of 1.21 g of [3-(3-fluorophenyl)-1-trityl-1H-5-indazolyl]methanol in 12 ml methylene chloride were added 0.45 ml of triethylamine and 0.23 ml of methanesulfonyl chloride, and the mixture was stirred at room temperature overnight. To the reaction mixture was added 150 ml of ethyl acetate. The mixture was sequentially washed with water, saturated aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The resulting crude crystals were recrystallized from diisopropyl ether, to give 1.13 g of the title compound as white crystals.
Reaction SMILES: ClC(OCC(C)C)=O.[Cl:9][C:10]1[CH:11]=[C:12]([NH:18][C@@H:19]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:20](O)=[O:21])[CH:13]=[CH:14][C:15]=1[C:16]#[N:17].CN1CCOCC1.[BH4-].[Na+]>C1COCC1.O>[Cl:9][C:10]1[CH:11]=[C:12]([NH:18][C@H:19]([CH2:20][OH:21])[CH2:23][C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH:13]=[CH:14][C:15]=1[C:16]#[N:17]
Reactant: CC(C)(C)OC(=O)C[C@H](Nc1ccc(C#N)c(Cl)c1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: O
Product: CC(C)(C)OC(=O)C[C@@H](CO)Nc1ccc(C#N)c(Cl)c1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 64.6 %

Procedure:
A solution of isobutyl chloroformate (2.01 g, 14.8 mmol) in THF (5 mL) was added dropwise to a solution of (2S)-2-[(3-chloro-4-cyanophenyl)amino]-4-[(1,1-dimethylethyl)oxy]-4-oxobutanoic acid (4.57 g, 14.1 mmol) and NMM (1.56 g, 15.5 mmol) in THF (50 mL) at −10° C. After stirring for 30 min, the reaction was filtered through a pad Celite and the filtrate was cooled to −10° C. To the cold filtrate, a solution of NaBH4 (0.80 g, 21 mmol) in H2O (10 mL) was added slowly and the reaction solution was stirred at −10° C. for 15 min and then at room temperature for 45 min. The reaction was quenched with aqueous NH4Cl and extracted with Et2O (2×). The organic extracts were washed with 5% Na2CO3, cold 0.1N HCl and H2O, dried over Na2SO4, filtered, and concentrated. The residue was purified via silica gel chromatography with 0% MeOH in CH2Cl2 grading to 3% MeOH in CH2Cl2 to afford the titled product (2.83 g, 64%) as a solid. 1H-NMR (CDCl3) δ: 1.45 (9H, s), 2.61 (2H, m), 3.79 (2H, d, J=4.4 Hz), 3.93 (1H, m), 6.55 (1H, dd, J=8 Hz, 4 Hz), 6.72 (1H, d, J=2 Hz), 7.41 (1H, d, J=8.8 Hz). LC-MS (ES) m/e 311.5 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:29])[C@H:11]([CH2:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:12][N:13]([O:16]C2CCCCO2)[CH:14]=[O:15])[C:5]([F:30])=[C:4]([N:31]([CH3:39])[CH2:32][C:33]2[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=2)[N:3]=1>C(O)(=O)C.O>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:29])[C@H:11]([CH2:23][CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28]2)[CH2:12][N:13]([OH:16])[CH:14]=[O:15])[C:5]([F:30])=[C:4]([N:31]([CH3:39])[CH2:32][C:33]2[CH:34]=[CH:35][N:36]=[CH:37][CH:38]=2)[N:3]=1
Reactant: CN(Cc1ccncc1)c1nc(Cl)nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OC2CCCCO2)c1F
Solvent: O
Solvent: CC(=O)O
Product: CN(Cc1ccncc1)c1nc(Cl)nc(NNC(=O)[C@H](CC2CCCC2)CN(O)C=O)c1F
Reaction time: 8 h
Yield: 30.5 %

Procedure:
[(2R)-3-(2-{2-Chloro-5-fluoro-6-[methyl(4-pyridinylmethyl)amino]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide (0.0958 g, 0.1701 mmol) was dissolved in acetic acid (8 mL) and water (2 mL). This reaction mixture was left to stir overnight. The volatiles were evaporated, and the resulting material was purified by RP-HPLC to provide [(2R)-3-(2-{2-chloro-5-fluoro-6-[methyl(4-pyridinylmethyl)amino]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl]hydroxyformamide as a beige solid (0.0249 g, 31%). LCMS: (M+H)+=480.1.