Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]1[C:4]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[CH3:22][O:23]C1C=CC2OC(C3C=CC(F)=CC=3)=CC=2C=1>>[CH3:22][O:23][C:9]1[CH:10]=[CH:3][C:4]2[O:11][C:12]([C:13]3[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=3)=[CH:6][C:5]=2[CH:8]=1
Reactant: COc1cccc(C=O)c1OCc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc2oc(-c3ccc(F)cc3)cc2c1
Product: COc1ccc2oc(-c3ccc([N+](=O)[O-])cc3)cc2c1
Yield: 89 %

Procedure:
Compound V was synthesized from compound (IV) as same procedure for Compound II in 89% yield.
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:17])([F:16])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C@H:13]([NH2:15])[CH3:14])=[N:11][CH:12]=1.[Br:18][C:19]1[CH:29]=[CH:28][C:22]([O:23][CH2:24][C:25](O)=[O:26])=[CH:21][CH:20]=1.C(N(CC)CC)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl.N>ClCCl>[Br:18][C:19]1[CH:29]=[CH:28][C:22]([O:23][CH2:24][C:25]([NH:15][C@@H:13]([C:10]2[CH:9]=[CH:8][C:7]([O:6][CH2:5][C:4]([F:3])([F:16])[F:17])=[CH:12][N:11]=2)[CH3:14])=[O:26])=[CH:21][CH:20]=1
Reactant: O=C(O)COc1ccc(Br)cc1
Reactant: C[C@@H](N)c1ccc(OCC(F)(F)F)cn1
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](NC(=O)COc1ccc(Br)cc1)c1ccc(OCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81 %

Procedure:
To a suspension of (R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethanamine 2HCl salt (173 mg, 0.79 mmol) and 2-(4-bromophenoxy)acetic acid (200 mg, 0.87 mmol) in dichloromethane (5 mL) were added triethylamine (400 mg, 3.9 mmol), EDC (180 mg, 0.94 mmol) and HOBT (60 mg, 0.39 mmol) respectively. The reaction mixture was stirred at room temperature for 18 hours. Sat. ammonia hydrochloride aqueous solution was added to the mixture. The organic layer was extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. After the filtration to separate solvent and sodium sulfate, the solvent was removed under reduced pressure to give the residue, which was applied to a silica gel chromatography column and eluted with a hexane/ethylacetate=2/1 (v/v) to furnish 276 mg (81% yield) of the title as a colorless oil;
Reaction SMILES: Cl[CH:2]([CH3:8])[C:3]([N:5]([CH3:7])[CH3:6])=[O:4].[CH2:9]([C:11]1[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:13][NH:14][CH:15]=1)[CH3:10].[CH3:22]C1C(C2C=CC=CC=2)=NNC=1>>[CH2:8]([CH:2]([N:14]1[CH:15]=[C:11]([CH2:9][CH3:10])[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:13]1)[C:3]([N:5]([CH3:7])[CH3:6])=[O:4])[CH3:22]
Reactant: Cc1c[nH]nc1-c1ccccc1
Reactant: CC(Cl)C(=O)N(C)C
Reactant: CCc1c[nH]nc1-c1ccccc1
Product: CCc1cn(C(CC)C(=O)N(C)C)nc1-c1ccccc1

Procedure:
Using the procedure of Example 1, but substituting 2-bromo-N,N-dimethylbutyramide for 2-chloro-N,N-dimethylpropionamide and 4-ethyl-3-phenylpyrazole for 4-methyl-3-phenylpyrazole, there was obtained α,4-diethyl-N,N-dimethyl-3-phenylpyrazole-1-acetamide, m.p. 77.5°-79° C.
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6](Cl)=[O:7])[CH:2]=[CH2:3].[C:9]([O:12][CH2:13][CH:14]([NH:20][C:21]([C:23]1[C:28]([I:29])=[C:27]([NH2:30])[C:26]([I:31])=[C:25]([C:32]([NH:34][CH:35]([CH2:41][O:42][C:43](=[O:45])[CH3:44])[CH2:36][O:37][C:38](=[O:40])[CH3:39])=[O:33])[C:24]=1[I:46])=[O:22])[CH2:15][O:16][C:17](=[O:19])[CH3:18])(=[O:11])[CH3:10]>CN(C)C(=O)C>[C:43]([O:42][CH2:41][CH:35]([NH:34][C:32]([C:25]1[C:26]([I:31])=[C:27]([NH:30][C:6](=[O:7])[CH2:5][O:4][CH2:1][CH:2]=[CH2:3])[C:28]([I:29])=[C:23]([C:21]([NH:20][CH:14]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[CH2:13][O:12][C:9](=[O:11])[CH3:10])=[O:22])[C:24]=1[I:46])=[O:33])[CH2:36][O:37][C:38](=[O:40])[CH3:39])(=[O:45])[CH3:44]
Reactant: CC(=O)OCC(COC(C)=O)NC(=O)c1c(I)c(N)c(I)c(C(=O)NC(COC(C)=O)COC(C)=O)c1I
Reactant: C=CCOCC(=O)Cl
Solvent: CC(=O)N(C)C
Product: C=CCOCC(=O)Nc1c(I)c(C(=O)NC(COC(C)=O)COC(C)=O)c(I)c(C(=O)NC(COC(C)=O)COC(C)=O)c1I
Temperature: 5 °C
Reaction time: 20 h
Yield: 97.2 %

Procedure:
Allyloxyacetyl chloride (9.0 g, 67 mmol) was added dropwise to a stirred solution of N,N'-bis[2-(acetyloxy)-1-[(acetyloxy)methyl]ethyl]-5-amino-2,4,6-triiodo-1,3-benzenedicarboxamide (30.0 g, 34 mmol) in N,N-dimethylacetamide (70 ml ) at 0°-5° C. The reaction mixture was stirred at 5° C. for 30 minutes and at room temperature for 20 hours. It was then slowly added dropwise to a well stirred mixture of ice-water (1.5 L), when a white solid separated out. This was collected by filtration, washed with water, and dried in vacuo to obtain N,N'-Bis[2-(acetyloxy)-1-[(acetyloxy)methyl]ethyl]-5-[(2-propenyloxy)acetyl ]amino-2,4,6-triiodo-1,3-benzenedicarboxamide as a white amorphous solid (32.1 g, 97% yield), m.p. 214°-16°.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12].C(N(CC)CC)C.C1C(=O)N([O:28][C:29]([CH2:31][CH2:32][S:33][S:34][C:35]2[N:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=O)C(=O)C1>C1(C)C=CC=CC=1>[N:40]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[S:34][S:33][CH2:32][CH2:31][C:29]([NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:28]
Reactant: O=C(CCSSc1ccccn1)ON1C(=O)CCC1=O
Reactant: NCCOCCOCCCC(=O)O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(O)CCCOCCOCCNC(=O)CCSSc1ccccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(2-(2-aminoethoxy)ethoxy)butanoic acid (Compound 4) (F.W. 312.37, 100 mg, 0.377 mmole) in 20 mL of anhydrous toluene was azetropically distilled under reduced pressure at 60° C. on a rotary evaporator. The azeotropic distillation was repeated with 20 mL of anhydrous toluene. Then, the resulting residue was dissolved in anhydrous DCM (20 ml). To the above solution was added N-succinimidyl-3-(2-pyridithio) propionate (Compound 5) (SDPD, F.W.265.3, 100 mg, 0.32 mmole) and triethylamine (105 μl, 0.75 mmole). The mixture was allowed to stand for overnight under stirring at room temperature. TLC showed the disappearance of SPDP. The reaction solution was washed with diluted phosphoric acid (pH4, 5 ml×2). The organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was subject to flash chromatography on a Biotage system, giving 140 mg of Compound 6, purity>95% (HPLC).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9](N)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[Cl:17][CH2:18][CH2:19][N:20]=[C:21]=[O:22].[NH2:23]P(=O)([O-])[O-]>C(Cl)(Cl)Cl>[CH2:6]([O:5][P:4]([CH:9]([N:20]([CH2:19][CH2:18][Cl:17])[C:21]([NH2:23])=[O:22])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: NP(=O)([O-])[O-]
Reactant: O=C=NCCCl
Reactant: CCOP(=O)(OCC)C(N)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CCOP(=O)(OCC)C(c1ccccc1)N(CCCl)C(N)=O
Temperature: 10 °C
Yield: 85 %

Procedure:
A solution of 0.05 mol of α-aminobenzylphosphonic acid diethyl ester in 30 ml of chloroform is cooled to 0° C. in an ice-bath and then a large excess (0.06 mol) of β-chloroethyl isocyanate is added. The temperature of the reaction is then maintained at 10° C. while continuing stirring until the reaction is complete. (Examination by thin layer chromatography is used to ascertain that the starting aminophosphonate has disappeared completely. After evaporation of the solvent under reduced pressure, the crystalline residue is taken up in ether and filtered, yielding 14.8 g of crystals. Yield: 85%; m.p.=82° C.
Reaction SMILES: [OH:1][CH:2]([C:14]1[S:15][CH:16]=[CH:17][N:18]=1)[CH:3]1[CH2:8][CH2:7][CH:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1.C1C(=O)N([Br:26])C(=O)C1>CN(C=O)C>[Br:26][C:16]1[S:15][C:14]([CH:2]([OH:1])[C@H:3]2[CH2:8][CH2:7][C@H:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]2)=[N:18][CH:17]=1.[Br:26][C:16]1[S:15][C:14]([CH:2]([OH:1])[C@@H:3]2[CH2:8][CH2:7][C@H:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]2)=[N:18][CH:17]=1
Reactant: CCOC(=O)C1CCC(C(O)c2nccs2)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H]1CC[C@@H](C(O)c2ncc(Br)s2)CC1
Product: CCOC(=O)[C@H]1CC[C@H](C(O)c2ncc(Br)s2)CC1
Temperature: 55 °C

Procedure:
The crude mixture of ethyl 4-[hydroxy(1,3-thiazol-2-yl)methyl]cyclohexanecarboxylate (34 g) was diluted with DMF (220 mL) and NBS (23 g, 129 mmol) was added. The resulting mixture was heated to 55° C. and stirred until the starting materials were consumed, at which point the heating mantle was removed. Water (220 mL) containing sodium sulfite (10 g) was added followed by EtOAc. The layers were separated, the organics washed a second time with water, then dried with MgSO4, filtered and concentrated in vacuo. The crude residue was absorbed on silica and purified by flash chromatography to afford racemic ethyl trans-4-[(5-bromo-1,3-thiazol-2-yl)(hydroxy)methyl]cyclohexanecarboxylate as a white solid and racemic ethyl cis-4-[(5-bromo-1,3-thiazol-2-yl)(hydroxy)methyl]cyclohexanecarboxylate as a yellow oil. Characterization data for the trans isomer: MS ESI calc'd. for C13H19BrNO3S [M+H]+ 348, 350. found 348, 350. 1H NMR (600 MHz, CDCl3) δ 7.53 (d, J=4.3, 1H), 4.66 (d, J=5.0, 1H), 4.06 (q, J=7.1, 2H), 2.20-2.16 (m, 1H), 1.97 (d, J=13.3, 2H), 1.80-1.72 (m, 2H), 1.68 (d, J=12.6, 1H), 1.43-1.31 (m, 2H), 1.25-1.13 (m, 5H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][CH2:11][CH2:12][NH2:13])=[N:2]1.[C:14]([O:18][C:19]([N:21](C1C=CC=CC=1)[CH2:22][C:23](O)=[O:24])=[O:20])([CH3:17])([CH3:16])[CH3:15].Cl.CN(C)CCCN=C=NCC.ON1[C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=2N=N1.C(N(CC)CC)C>ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][CH2:11][CH2:12][NH:13][C:23](=[O:24])[C@@H:22]([NH:21][C:19](=[O:20])[O:18][C:14]([CH3:15])([CH3:16])[CH3:17])[C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[N:2]1
Reactant: NCCNc1nsc2ccccc12
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](C(=O)NCCNc1nsc2ccccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.5 %

Procedure:
A mixture of N1-(benzo[d]isothiazol-3-yl)ethane-1,2-diamine (600 mg, 3.1 mmol), N α (t-butoxycarbonyl)phenylglycine (850 mg, 3.4 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (650 mg, 3.4 mmol), 1-hydroxybenzotriazole (520 mg, 3.4 mmol) and triethylamine (950 μL, 6.8 mmol) in dichloromethane (50 mL) was allowed to stir at room temperature overnight. The reaction mixture was washed successively with 1N aqueous hydrochloric acid, saturated sodium bicarbonate solution and water, then dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure. Purification by flash column chromatography, on silica gel, eluting with a mixture of 30% ethyl acetate in hexanes and selected fractions were combined and concentrated under reduced pressure to give (S)-tert-butyl 2-(2-(benzo[d]isothiazol-3-ylamino)ethylamino)-2-oxo-1-phenylethylcarbamate (720 mg) as a white solid. 1H NMR (300 MHz, CDCl3): 7.78 (d, 1H), 7.61 (d, 1H), 7.49 (t, 1H), 7.30 (t, 1H), 7.21 (m, 2H), 7.18 (m, 2H), 6.95 (t, 1H), 5.66 (m, 2H), 5.10 (broad s, 1H), 3.62 (m, 4H), 1.39 ppm (s, 9H). MW=427 confirmed by LC-MS, tr=13.38 min (Method Y) MH+=428.
Reaction SMILES: [OH2:1].O.O.O.O.O.O.O.O.O.C(=O)([O-])[O-].[Na+].[Na+].[F:17][C:18]1[CH:19]=[CH:20][C:21]2[N:27]3[CH:28]=[N:29][C:30]([CH:31]=O)=[C:26]3[CH2:25][N:24]([CH3:33])[C:23](=[O:34])[C:22]=2[CH:35]=1.Cl.[NH2:37]O>O>[F:17][C:18]1[CH:19]=[CH:20][C:21]2[N:27]3[CH:28]=[N:29][C:30]([CH:31]=[N:37][OH:1])=[C:26]3[CH2:25][N:24]([CH3:33])[C:23](=[O:34])[C:22]=2[CH:35]=1
Reactant: NO
Reactant: CN1Cc2c(C=O)ncn2-c2ccc(F)cc2C1=O
Reactant: O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CN1Cc2c(C=NO)ncn2-c2ccc(F)cc2C1=O
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A solution of 4.14 g (14.5 mmol) of sodium carbonate decahydrate in 20 ml of water is added dropwise to a mixture of 3.0 g (11.6 mmol) of 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxaldehyde, 0.99 g (14.5 mmol) of hydroxylamine hydrochloride and 60 ml of water, the mixture is stirred at 70° C. for 1 hour, cooled in an ice-bath and the separated material is filtered off under suction and washed with water. The still moist substance is recrystallised from ethanol and yields 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxaldehyde-3-oxime of melting point 247°-250° C.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][NH2:13])[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3].[Cl:14][C:15]1[N:20]=[C:19]([NH:21][C:22]2[CH:23]=[CH:24][C:25]3[O:30][C:29]([CH3:34])([C:31](O)=[O:32])[C:28](=[O:35])[NH:27][C:26]=3[CH:36]=2)[C:18]([F:37])=[CH:17][N:16]=1.C(N(C(C)C)C(C)C)C>CN(C=O)C.C(OCC)(=O)C>[Cl:14][C:15]1[N:20]=[C:19]([NH:21][C:22]2[CH:23]=[CH:24][C:25]3[O:30][C:29]([CH3:34])([C:31]([NH:13][CH2:12][CH2:11][C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([N+:2]([O-:4])=[O:3])[CH:6]=4)=[O:32])[C:28](=[O:35])[NH:27][C:26]=3[CH:36]=2)[C:18]([F:37])=[CH:17][N:16]=1
Reactant: CC1(C(=O)O)Oc2ccc(Nc3nc(Cl)ncc3F)cc2NC1=O
Reactant: NCCc1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C(=O)NCCc2cccc([N+](=O)[O-])c2)Oc2ccc(Nc3nc(Cl)ncc3F)cc2NC1=O
Reaction time: 16 h
Yield: 91.8 %

Procedure:
2-(3-nitrophenyl)ethanamine hydrochloride (100.00 mg; 0.49 mmol; 1.00 eq.), 6-[(2-chloro-5-fluoropyrimidin-4-yl)amino]-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid (SYN5052A) (174.06 mg; 0.49 mmol; 1.00 eq.), o-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetra-methyluronium hexafluorophosphate (375.28 mg; 0.99 mmol; 2.00 eq.) and N-ethyl-N-isopropylpropan-2-amine (0.32 ml; 1.97 mmol; 4.00 eq.) are placed into a scintillation vial equipped with a stir bar. The mixture is taken up in DMF (3.00 ml). The reaction mixture is stirred for 16 hours. Upon completion, the reaction mixture is diluted with ethyl acetate (100 mL) and extracted with brine solution. The organic layer is then dried over magnesium sulfate, filtered, concentrated and purified via Prep HPLC using a gradient of 10-50% acetonitrile in water with 0.1% trifluoroacetic acid modifier to give 6-[(2-chloro-5-fluoropyrimidin-4-yl)amino]-2-methyl-N-[2-(3-nitrophenyl)ethyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxamide (10) (226.4 mg; 0.45 mmol; 91.6%);
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:26]=[CH:25][C:19]([O:20][CH2:21][C:22]([OH:24])=O)=[CH:18][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:20][CH2:21][C:22](=[O:24])[NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:25][CH:26]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)COc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Reactant: Nc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(COc1ccc(CCCCNC(=O)OCc2ccccc2)cc1)Nc1ccccc1
Yield: 99.1 %

Procedure:
A mixture of [4-(4-benzyloxycarbonylaminobutyl)phenoxy]acetic acid (300 mg, 0.84 mmol), aniline (0.15 mL, 1.70 mmol), DMAP (60 mg, 0.50 mmol) and EDC.HCI (320 mg, 1.70 mmol) in CH2Cl2 (30 mL) was stirred at room temperature for 66 h. The reaction mixture was concentrated under vacuum and the residue was subjected to flash silica gel column chromatography eluting with methanol/CH2Cl2 (1:99, v/v) to give the desired amide 18 as a white solid (360 mg, 99% yield). 1H NMR (300 MHz, CDCl3) δ 8 1.55 (m, 4H), 2.60 (m, 2H), 3.20 (m, 2H), 4.58 (s, 2H), 4.70 (br s, 1H), 5.10 (s, 2H), 6.88 (d, 2H), 7.15. (m, 3H), 7.35 (m, 7H), 7.58 (d, 2H), 8.25 (s, 1H). m/z (ESI): 433 [C26H28N2O4 +H]+.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30].O>C(Cl)Cl>[CH3:28][S:29]([N:16]1[CH2:17][CH2:18][N:13]([C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][CH2:4][CH2:3][C:2]([F:1])([F:19])[F:20])=[CH:8][CH:9]=2)[CH2:14][CH2:15]1)(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: FC(F)(F)CCCOc1ccc(N2CCNCC2)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCN(c2ccc(OCCCC(F)(F)F)cc2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of the 1-[4-(4,4,4-trifluorobutoxy)phenyl]piperazine product from Part B (5 g, 17 mmol) in methylene chloride (50 mL) was added triethyl amine (4 mL). The mixture was cooled to 0° C. Methane sulfonyl chloride (2.4 g, 21 mmol) in a solution of methylene chloride (10 mL) was then added dropwise. After 2 hr, the reaction was complete. The solvent was removed under reduced pressure to produce a solid residue. To this solid was added water (100 mL). The resulting mixture was filtered and washed with water, and then dried under high vacuum to produce 6 g (95% yield) of the desired compound in the form of a tan solid. Proton NMR and MS were consistent with the desired structure.
Reaction SMILES: [C:1]1([C:7]([OH:12])([CH3:11])[CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:13](Cl)([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14].C(N(CC)CC)C.O>C(Cl)Cl>[CH3:20][C:19]1[CH:21]=[CH:22][C:16]([S:13]([O:10][CH2:9][CH2:8][C:7]([OH:12])([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:11])(=[O:15])=[O:14])=[CH:17][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(O)(CCO)c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCC(C)(O)c2ccccc2)cc1
Reaction time: 8 h
Yield: 47.2 %

Procedure:
To a solution of 3-phenylbutane-1,3-diol (68 g, 0.41 mol) in dry CH2Cl2 (500 mL) was added dropwise a solution of TsCl (78 g, 0.41 mol) and triethylamine (71 mL, 0.45 mol) in dry CH2Cl2 (500 mL) at 0° C. The mixture was stirred overnight. The mixture was poured into water and separated. The aqueous layer was extracted with CH2Cl2 (200 mL) twice. The organic layer was combined, washed with brine, dried over anhydrous Na2SO4 and concentrated to give the crude product. The crude product was purified by column chromatography to give 3-hydroxy-3-phenylbutyl 4-methylbenzenesulfonate (62 g, 42%). 1H NMR (400 MHz, CDCl3): δ=1.55 (s, 3H), 1.93 (w, 1H), 2.19˜2.24 (q, 2H), 2.45 (s, 3H), 3.87˜4.01 (m, 1H), 4.09˜4.16 (m, 1H), 7.19˜7.34 (m, 7H), 7.68˜7.76 (d, 2H).
Reaction SMILES: [CH:1]1([O:6][C:7](=[O:49])[C@@H:8]([NH:16][C:17](=[O:48])[CH2:18][CH2:19][C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[NH:25][C:24]([C:29](=[O:47])[NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37](=[O:46])[NH:38][O:39]C2CCCCO2)=[CH:23]3)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(O)(C(F)(F)F)=O.C(Cl)Cl.CO>[CH:1]1([O:6][C:7](=[O:49])[C@@H:8]([NH:16][C:17](=[O:48])[CH2:18][CH2:19][C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[NH:25][C:24]([C:29](=[O:47])[NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37](=[O:46])[NH:38][OH:39])=[CH:23]3)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CCCCCCNC(=O)c1cc2cc(CCC(=O)N[C@@H](Cc3ccccc3)C(=O)OC3CCCC3)ccc2[nH]1)NOC1CCCCO1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=C(CCCCCCNC(=O)c1cc2cc(CCC(=O)N[C@@H](Cc3ccccc3)C(=O)OC3CCCC3)ccc2[nH]1)NO
Reaction time: 0.5 h
Yield: 11 %

Procedure:
(S)-3-Phenyl-2-(3-{2-[6-(tetrahydro-pyran-2-yloxycarbamoyl)-hexyl-carbamoyl]-1H-indol-5-yl}-propionylamino)-propionic acid cyclopentyl ester (200 mg. 0.297 mmol) was stirred at room temperature for 3.5 h in TFA/DCM/MeOH (1.5 ml/15 ml/15 ml). Further TFA (0.3 ml) was added and the reaction stirred for a further 30 minutes. The solution was concentrated in vacuo, resuspended in DCM and the solvent removed (×3). The crude material was purified by prep HPLC to give pure compound (100) (19.3 mg), LCMS purity 100%, m/z 591 [M++H]+, 1H NMR (400 MHz, MeOD), δ: 1.27-1.70 (16 H, m, alkyl), 1.97 (2H, t, CH2), 2.40 (2H, t, J=7.84 Hz, CH2), 2.76-2.85 (4H, m, 2×CH2), 3.25 (2H, t, J=7 Hz, CH2), 4.41 (1H, m, NHCHCO, 4.95 (1H, m, CH), 6.85 (1 H, s, CH), 6.95 (3H, m, Ar), 7.05 (3H, m, Ar), 7.20-7.26 (2H, s+d, J=8.5 Hz, Ar)
Reaction SMILES: C([O:5][C:6](=[O:21])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[C:10]([C:18](=[O:20])[NH2:19])=[CH:9]1)(C)(C)C.C(O)(C(F)(F)F)=O.CO>C(Cl)Cl>[C:18]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[N:8]([CH2:7][C:6]([OH:21])=[O:5])[CH:9]=1)(=[O:20])[NH2:19]
Reactant: CC(C)(C)OC(=O)Cn1cc(C(N)=O)c2cc(Cl)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: NC(=O)c1cn(CC(=O)O)c2ccc(Cl)cc12
Reaction time: 2 h

Procedure:
To a solution of (3-carbamoyl-5-chloro-indol-1-yl)-acetic acid tert-butyl ester (455 mg, 0.973 mmol) in CH2Cl2 (6.0 mL) was added TFA (3.0 mL) at RT and stirring was continued for 2 h. Methanol was then added to the reaction mixture and volatiles were removed in vacuo. The residue was taken up in methanol and concentrated again under reduced pressure. The residue was dissolved in 1N aqueous NaOH and washed with CH2Cl2 (3×). The water phase was acidified to pH 2 by adding 6N aqueous HCl to form a white suspension. The precipitate was filtered off, washed with water and dried in vacuo to afford the crude title compound as a white solid. MS (LC/MS): 253 [M+H]+, 505 [2M+H]+; tR (HPLC conditions b): 3.99 min. The product was used in the next reaction step without further purification.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:9][C@@H:8]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:7][C@H:6]1[N:15]1[C:24]2[N:23]=[CH:22][N:21]=[C:19](O)[C:18]=2[N:17]=[CH:16]1)(=[O:3])[CH3:2].CN(C)C=O.S(Cl)([Cl:32])=O.O>C(Cl)Cl>[Cl:32][C:19]1[N:21]=[CH:22][N:23]=[C:24]2[C:18]=1[N:17]=[CH:16][N:15]2[C@@H:6]1[O:7][C@H:8]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[CH2:9][C@H:5]1[O:4][C:1](=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)OC[C@@H]1C[C@@H](OC(C)=O)[C@H](n2cnc3c(O)ncnc32)O1
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OC[C@@H]1C[C@@H](OC(C)=O)[C@H](n2cnc3c(Cl)ncnc32)O1
Temperature: 0 °C
Yield: 89.9 %

Procedure:
32.7 g (97.2 mmols) of 2′,5′-di-O-acetyl-3′-deoxyinosine was suspended in 449 ml of methylene chloride in a 1-liter reactor, to which were added 30.1 ml (389 mmols) of dimethylformamide and 28.0 ml (389 mmols) of thionyl chloride, and reacted for about 7 hours while heating under reflux. The reaction mixture was cooled to 0° C., and then dropwise added to 500 ml of water that had been cooled at 0° C. to stop the reaction. The reaction mixture was separated into layers, and the organic layer was taken out, and washed with water, an aqueous saturated solution of sodium hydrogencarbonate and a saturated saline solution in that order. The solvent was evaporated, and 31.0 g of an oily product was obtained. This crude product was directly subjected to the next reaction.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([NH:25][C:26]3[N:31]=[C:30]([CH:32]4[CH2:34][CH2:33]4)[C:29]([F:35])=[CH:28][N:27]=3)[CH:19]=2)=[CH:16][N:17]=1)([OH:12])[CH3:11])(C(C)(C)C)(C)C.Cl>CO>[CH:32]1([C:30]2[C:29]([F:35])=[CH:28][N:27]=[C:26]([NH:25][C:20]3[CH:19]=[C:18]([C:15]4[S:14][C:13]([C:10]([OH:12])([CH3:11])[CH2:9][OH:8])=[N:17][CH:16]=4)[CH:23]=[C:22]([F:24])[CH:21]=3)[N:31]=2)[CH2:33][CH2:34]1
Reactant: CC(O)(CO[Si](C)(C)C(C)(C)C)c1ncc(-c2cc(F)cc(Nc3ncc(F)c(C4CC4)n3)c2)s1
Agent: Cl
Solvent: CO
Product: CC(O)(CO)c1ncc(-c2cc(F)cc(Nc3ncc(F)c(C4CC4)n3)c2)s1
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a solution of the product of Step 5 (150 mg, 0.289 mmol) in methanol (4 mL) was added HCl (4.0 M in dioxane) (0.072 mL, 0.289 mmol). After 30 minutes, the reaction mixture was concentrated. The residue was purified by preparative HPLC Reverse phase (C-18), eluting with acetonitrile/water 0.05% TFA to give 2-(5-{3-[(4-cyclopropyl-5-fluoropyrimidin-2-yl)-amino]-5-fluorophenyl}-1,3-thiazol-2-yl)propane-1,2-diol (95 mg, 0.24 mmol, 81%). MS ESI: [M+H]+ m/z 405.1. 1H NMR (600 MHz, DMSO-d6) 0.83 (s, 1H); 8.41 (s, 1H); 8.01 (s, 1H); 7.75 (s, 1H); 7.53 (d, J=11.4 Hz, 1H); 7.06 (d, J=9.6 Hz, 1H); 5.89 (s, 1H); 4.89 (s, 1H); 3.52 (s, 2H); 2.29-2.22 (m, 1H); 1.43 (s, 3H); 1.20-1.12 (m, 4H). rhSYK activity=+++