Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.[NH2:28][C:29]1[CH:30]=[C:31]([CH:35]([NH:37][C:38]2[C:47]3[C:42](=[C:43]([C:48]([NH2:50])=[O:49])[CH:44]=[CH:45][CH:46]=3)[N:41]=[CH:40][N:39]=2)[CH3:36])[CH:32]=[CH:33][CH:34]=1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([NH:28][C:29]1[CH:30]=[C:31]([CH:35]([NH:37][C:38]2[C:47]3[C:42](=[C:43]([C:48]([NH2:50])=[O:49])[CH:44]=[CH:45][CH:46]=3)[N:41]=[CH:40][N:39]=2)[CH3:36])[CH:32]=[CH:33][CH:34]=1)=[O:7]
Reactant: CC(Nc1ncnc2c(C(N)=O)cccc12)c1cccc(N)c1
Reactant: COc1ccc(C(=O)O)cc1F
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)Nc2cccc(C(C)Nc3ncnc4c(C(N)=O)cccc34)c2)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.5 %

Procedure:
To a solution of 3-fluoro-4-methoxybenzoic acid (26.00 mg; 0.15 mmol; 1.00 eq.) in DMF were added bis(2-oxo-1,3-oxazolidin-3-yl)phosphinic chloride (35.01 mg; 0.14 mmol; 0.90 eq.), 4-{[1-(3-aminophenyl)ethyl]amino}quinazoline-8-carboxamide (41.33 mg; 0.13 mmol; 0.88 eq.), and N-ethyl-N-isopropylpropan-2-amine (0.07 ml; 0.38 mmol; 2.50 eq.). The reaction mixture was stirred overnight at RT. Purified the crude by HPLC to obtain 20 mg of the title product in 28% yield. MS (M+1) 460
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1F)[CH:17]=[O:18]>>[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:9]([F:10])([F:11])[F:12])[CH:4]=1)[CH:17]=[O:18]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: Oc1ccc(F)c(C(F)(F)F)c1
Product: O=Cc1ccc(Oc2ccc(F)c(C(F)(F)F)c2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 4-fluoro-3-(trifluoromethyl)phenol and 3,4-difluorobenzaldehyde.
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:31])[CH2:12][S:13][CH:14]2[C:18]([CH3:19])=[C:17]([CH3:20])[C:16](=[O:21])[N:15]2[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[N:6][CH:5]=1.N[C:34]1[CH:39]=C(CC)C=CN=1>>[CH2:34]([C:9]1[CH:4]=[CH:5][N:6]=[C:7]([NH:10][C:11](=[O:31])[CH2:12][S:13][CH:14]2[C:18]([CH3:19])=[C:17]([CH3:20])[C:16](=[O:21])[N:15]2[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[CH:8]=1)[CH3:39]
Reactant: CCc1ccnc(N)c1
Reactant: COC(=O)c1ccc(NC(=O)CSC2C(C)=C(C)C(=O)N2Cc2ccc(OC)cc2)nc1
Product: CCc1ccnc(NC(=O)CSC2C(C)=C(C)C(=O)N2Cc2ccc(OC)cc2)c1

Procedure:
The product from Example 1, Part C (0.3 g, 0.93 mmol) and 2-amino-4-ethylpyridine (0.171 g, 1.4 mmol) were converted to the title compound by the method described in Part B of Example 16 (121 mg, 30%). 1H NMR (300 MHz, CDCl3) δ 8.53 (broad s, 1H); 8.15 (d, J=5.16 Hz, 1H); 7.99 (s, 1H); 7.23 (d, J=8.4 Hz, 2H); 6.92 (m, 1H); 6.84 (d, J=8.5 Hz, 2H); 5.11 (d, J=15 Hz, 1H); 4.61 (s, 1H); 4.16 (d, 15 Hz, 1H); 3.77 (s, 3H); 2.90 (s, 2H); 2.67 (q, J=7.4 Hz, 2H); 1.95 (s, 3H); 1.84 (s, 3H); 1.27 (t, J=7.6 Hz, 3H). MS: m/z (MH+) 426.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][NH:17]3)=[CH:11][C:10]=2[CH3:22])=[N:6][CH:7]=1.C(N(CC)CC)C.Br[CH2:38][C:39]([NH2:41])=[O:40]>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[C:10]([CH3:22])=[CH:11][C:12]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][N:17]3[CH2:38][C:39]([NH2:41])=[O:40])=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCCCN4)cc3C)ncc2Cl)n[nH]1
Reactant: NC(=O)CBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCCCN4CC(N)=O)cc3C)ncc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 5-Chloro-N2-(2,5-dimethyl-4-(piperidin-2-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (0.12 mmol) and triethylamine (83 uL, 0.6 mmol) in DMF (1.5 mL), was added 2-bromoacetamide (35 mg, 0.24 mmol). The mixture was stirred at room temperature for 3 h. The reaction was filtered and the filtrate was purified by RP-HPLC to afford 2-(2-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5-dimethylphenyl)piperidin-1-yl)acetamide as a white solid; 1H NMR (400 MHz, MeOD-d4) 8.09 (s, 1H), 7.65 (d, 1H), 7.43 (s, 1H), 6.41 (s, 1H), 4.79-4.74 (m, 2H), 3.83-3.48 (m, 2H), 2.71 (s, 3H), 2.42 (s, 3H), 2.34 (s, 6H), 2.15-1.84 (m, 7H); ESMS m/z 469.2 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([CH2:11][Br:12])[CH:8]=[C:7]([CH2:13]Br)[CH:6]=1)[CH3:2].[C:16]1([OH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:6]=[C:7]([CH2:13][O:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:8]=[C:9]([CH2:11][Br:12])[CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(CBr)cc(CBr)c1
Reactant: Oc1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(CBr)cc(COc2ccccc2)c1

Procedure:
The subtitle compound was prepared from 3,5-bis[bromomethyl]benzoic acid ethyl ester (5.18 g) and phenol (1.45 g) in dimethylformamide (10 ml) by the method of example 7 step (i). Yield after chromatography, eluting with 10% ethyl acetate in isohexane, 2.13 g of a mixture containing 15% product and 85% diphenoxy compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@@H:5]([CH2:7][OH:8])[NH2:6].C(N(CC)CC)C.[C:17](Cl)(=[O:19])[CH3:18]>ClCCl>[CH3:2][O:3][C:4](=[O:9])[C@@H:5]([CH2:7][OH:8])[NH:6][C:17](=[O:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: COC(=O)[C@H](N)CO
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](CO)NC(C)=O
Temperature: -10 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
D-Serine methyl ester hydrochloride (100 g, 0.6430 mole) was suspended in 500 ml dichloromethane. To this was added triethylamine (136.6 g, 1.35 mole) at 0-5° C., followed by acetyl chloride (53.06 g, 0.6751 mole) drop wise at −10° C. The reaction mixture was stirred at −10° C. for 3 hours, filtered to remove salts and the filtrate was evaporated. The resulting residue was suspended in 400 ml ethyl acetate and stirred for one hour. Salts were filtered and the ethyl acetate layer was concentrated under reduced pressure to get N-acetyl D-serine methyl ester as an oil (93.22 g, Yield: 90%, HPLC: 98.7%),
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[N:37][CH:36]=1>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:34]([C:35]3[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=3)=[O:41])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4cccnc4)c3C2=O)C(=O)N1
Yield: 64.7 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.98 g, 6.48 mmol) was added to stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.6 g, 1.85 mmol) in CH3CN (50 ml). After stirring for 20 min, nicotinoyl chloride (0.41 g, 2.22 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 ml). The CH2Cl2 solution was washed with H2O (30 ml), brine (30 ml) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by flash chromatography (SiO2, CH2Cl2: CH3OH 97.5:2.5) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}-3-pyridylcarboxamide (0.47 g, 64%) as a white solid: mp 148-151° C.; 1H NMR (DMSO-d6) δ d 11.16 (s, 1H), 9.36 (t, J=5.6 Hz, 1H), 9.09 (d, J=1.25 Hz, 1H), 8.75-8.73 (m, 1H), 8.25 (d, J=8.0 Hz, 1H), 7.84-7.76 (m, 3H), 7.57-7.52 (m, 1H), 5.22-5.15 (dd, J=5.4 and 12.7 Hz, 1H), 4.96 (d, J=5.6 Hz, 2H), 2.92-2.85 (m, 1H), 2.65-2.50 (m, 2H), 2.11-2.06 (m, 1H); 13C NMR (DMSO-d6) δ d 172.72, 169.80, 167.51, 166.94, 165.23, 152.02, 148.44, 138.86, 135.10, 134.83, 133.20, 131.55, 129.48, 127.20, 123.49, 121.95, 48.89, 38.33, 30.93, 21.98; Anal. Calcd. For C20H16N4O5+0.28H2O: C, 60.45; H, 4.20; N, 14.10. Found: C, 60.29; H, 4.28; N, 13.82.
Reaction SMILES: Cl.Cl.[N:3]1([CH2:8][CH2:9][NH2:10])[CH:7]=[N:6][CH:5]=[N:4]1.[OH-].[Na+].[Cl:13][C:14]1[C:15]2[CH:25]=[CH:24][CH:23]=[CH:22][C:16]=2[S:17][C:18]=1[C:19](Cl)=[O:20]>C(Cl)Cl>[Cl:13][C:14]1[C:15]2[CH:25]=[CH:24][CH:23]=[CH:22][C:16]=2[S:17][C:18]=1[C:19]([NH:10][CH2:9][CH2:8][N:3]1[CH:7]=[N:6][CH:5]=[N:4]1)=[O:20]
Reactant: NCCn1cncn1
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(NCCn1cncn1)c1sc2ccccc2c1Cl
Reaction time: 16 h

Procedure:
A mixture of about 1.85 g of 1H-1,2,4-triazole-1ethanamine dihydrochloride, about 50 ml of methylene chloride, about 30 ml of 1N sodium hydroxide and about 2.3 g of 3-chlorobenzo-[b]thiophene carbonyl chloride was stirred for about 16 hours. A 50 ml portion of methylene chloride and about 5 ml of 1N sodium hydroxide were added and the layers were separated. The organic layer was washed twice with water dried and concentrated, giving the desired compound, mp 151°-152° C.
Reaction SMILES: CC(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=O)[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])C=2OC)[CH2:10][CH2:9]1)=O)(C)C.[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].C[CH2:34][O:35]CC>>[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].[CH3:22][O:21][C:17]1[C:18]([O:35][CH3:34])=[CH:19][CH:20]=[CH:15][C:14]=1[C:11]1([CH:28]=[O:30])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: COc1cccc(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c1OC
Reactant: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(C2(C=O)CCNCC2)c1OC
Reaction time: 0.75 h

Procedure:
4-(2,3-Dimethoxybenzoyl)-1-piperidinecarboxylic acid 1,1-dimethylethyl ester (7.75 g, 22.2 mmol) was dissolved in trifluoroacetic acid (50 mL, 650 mmol) and stirred for 45 minutes. The entire solution was poured into ether (900 mL) and allowed to stand overnight. Filtration yielded 4-(2,3-dimethoxyphenyl)-4-piperidinylmethanone trifluoroacetate as fine white needles, m.p. 123° C. Anal. Calcd for C14H19NO3.CF3CO2H: C, 52.89; H, 5.55; N, 3.86. Found: C, 52.77; H, 5.62; N, 3.82.
Reaction SMILES: [CH2:1]([OH:9])[CH:2](O)[CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[CH2:10]([O:12]COCC)C.C1(C)C(S(O)(=O)=O)=CC=CC=1>>[OH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:10][O:12][O:9][CH2:1]1
Reactant: OCCCCC(O)CO
Reactant: CCOCOCC
Agent: Cc1ccccc1S(=O)(=O)O
Product: OCCCCC1COOC1

Procedure:
13.4 g of commercial 1,2,6-hexanetriol are added to 12.4 ml of diethoxymethane and the mixture is refluxed in the presence of 500 mg of toluenesulfonic acid acting as a transacetalisation catalyst. The ethanol is evaporated at 80° C. and the 4-(4-hydroxybutyl)-1,2-dioxolane obtained is purified by distillation. 7.3 g of this product and 4.6 g of epichlorhydrine are reacted in the presence of 2.8 g of potassium hydroxide (powder) and tetrabutylammonium chloride, to form the monomer 4-[(4-glycidyloxy)-butyl]-1,3-dioxolane
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([F:49])[C:42]=3[F:50])[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH2:51][O:52][Si](C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C>CO>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([F:49])[C:42]=3[F:50])[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH2:51][OH:52])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(Cc2cc([C@]3(OC)O[C@H](CO[Si](C)(C)C)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)c(F)c1F
Solvent: CC(=O)Cl
Solvent: CO
Product: COc1ccc(Cc2cc([C@]3(OC)O[C@H](CO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)c(F)c1F
Reaction time: 1 h
Yield: 60.2 %

Procedure:
[[(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methoxy]trimethylsilane 21 (2.4 g, 2.84 mmol) was dissolved in 20 mL methanol and stirred for 1 hour after addition of acetyl chloride (30 μL, 0.43 mmol). The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography with elution system B to obtain the title compound [(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl]phenyl]-6-meth oxy-tetrahydropyran-2-yl]methanol 2j (1.25 g, yellow solid), with yield: 60.4%.
Reaction SMILES: C(OC([NH:8][C:9]1[C:10]([CH3:21])=[N:11][C:12]([O:16][CH2:17][C:18]([OH:20])=O)=[N:13][C:14]=1[CH3:15])=O)(C)(C)C.[CH:22]1([N:27]2[CH2:32][CH2:31][CH:30]([NH:33][CH3:34])[CH2:29][CH2:28]2)[CH2:26][CH2:25][CH2:24][CH2:23]1>>[NH2:8][C:9]1[C:14]([CH3:15])=[N:13][C:12]([O:16][CH2:17][C:18]([N:33]([CH:30]2[CH2:31][CH2:32][N:27]([CH:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)[CH2:28][CH2:29]2)[CH3:34])=[O:20])=[N:11][C:10]=1[CH3:21]
Reactant: Cc1nc(OCC(=O)O)nc(C)c1NC(=O)OC(C)(C)C
Reactant: CNC1CCN(C2CCCC2)CC1
Product: Cc1nc(OCC(=O)N(C)C2CCN(C3CCCC3)CC2)nc(C)c1N

Procedure:
The title compound was synthesized from Compound 9 and 1-cyclopentyl-N-methylpiperidine-4-amine in the same manner as in Example 64.
Reaction SMILES: [CH3:1][C@H:2]([O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[C:12]([O:24]C)[N:13]2[CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]2)=[C:9]([NH2:26])[N:8]=1)[CH2:3][CH2:4][CH3:5].Cl.O1CCOCC1>CO>[NH2:26][C:9]1[N:8]=[C:7]([O:6][C@@H:2]([CH3:1])[CH2:3][CH2:4][CH3:5])[N:15]=[C:14]2[C:10]=1[NH:11][C:12](=[O:24])[N:13]2[CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]1
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCCNC3)c2n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCC[C@H](C)Oc1nc(N)c2[nH]c(=O)n(CCC3CCCNC3)c2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 63.6 %

Procedure:
To a solution of 2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-9-[2-(3-piperidinyl)ethyl]-9H-purin-6-amine (35 mg, 0.097 mmol) in methanol (4 ml) was added 4M HCl in dioxane (1.5 ml, 6.00 mmol) and the mixture was allowed to stir at room temperature for 1.5 hours. The reaction was then dried under a stream of nitrogen in the Radleys blowdown apparatus to give the crude product. This was redissolved in methanol (˜5 mL) and passed down a 2 g aminopropyl (—NH2) SPE cartridge. The filtrate was dried under a stream of nitrogen in Radleys blowdown apparatus. The sample was dissolved in 1:1 MeOH:DMSO (1 ml) and purified by Mass Directed AutoPrep (Method A). The solvent was dried under a stream of nitrogen in the Radleys blowdown apparatus to give the title compound as an off-white solid (21.5 mg). LCMS (System D): tRET=2.25 min; MH+ 349
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=2)=[O:26])[CH:22]=[C:21]([Cl:36])[C:3]=1[C:4]([NH:6][C@H:7]([C:17]([O:19]C)=[O:18])[CH2:8][NH:9][C:10]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)=[O:11])=[O:5].[OH-].[Na+]>CO.O>[Cl:1][C:2]1[CH:24]=[C:23]([C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=2)=[O:26])[CH:22]=[C:21]([Cl:36])[C:3]=1[C:4]([NH:6][C@H:7]([C:17]([OH:19])=[O:18])[CH2:8][NH:9][C:10]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)=[O:11])=[O:5]
Reactant: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1c(Cl)cc(C(=O)NCc2cccc(O)c2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(NCc1cccc(O)c1)c1cc(Cl)c(C(=O)N[C@@H](CNC(=O)c2cccs2)C(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
A mixture of N-[2,6-dichloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-[(thiophene-2-carbonyl)amino]-L-alanine, methyl ester (2.41 g, 4.4 mmol) in methanol (100 Ml) and sodium hydroxide (0.35 g, 8.8 mmol) in water (2 Ml) was stirred at room temperature overnight and then the solvents were evaporated. The residue was partitioned between water and ethyl acetate and the ethyl acetate layer was discarded. The aqueous layer was acidified with 1 M HCl, and extracted twice with ethyl acetate. The combined organic extracts were washed with brine, and the product started to precipitate. The solvents were evaporated from the organic layer, and dichloromethane/hexanes was added to the residue. The solid was filtered off, dried overnight under high vacuum, and taken up again in dichloromethane/hexanes. The solid was filtered off, and then dried overnight under high vacuum to give N-[2,6-dichloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-[(thiophene-2-carbonyl)amino]-L-alanine (2.10 g, 89%) as a white solid.
Reaction SMILES: [CH3:1][CH:2]([OH:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[CH3:17][S:18](Cl)(=[O:20])=[O:19].C(N(C(C)C)CC)(C)C>>[CH3:17][S:18]([O:16][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH3:1])(=[O:20])=[O:19]
Reactant: CCCCCCCCCCCCCC(C)O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCCCCC(C)OS(C)(=O)=O
Yield: 95 %

Procedure:
The 2-methanesulfonyloxypentadecane was prepared from 2-pentadecanol (25 g, 109 mmol), methanesulfonylchloride (11.8 ml, 152 mmol) and diisopropylethylamine (22.8 ml, 131 mmol) as previously described in 95% yield.
Reaction SMILES: [F:1][C:2]1[N:3]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][OH:10])[N:6]=1.[C:30](Cl)(=[O:32])[CH3:31].O>N1C=CC=CC=1>[C:30]([O:10][CH2:9][CH2:8][CH2:7][C:5]1[N:6]=[C:2]([F:1])[N:3]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:4]=1)(=[O:32])[CH3:31]
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Reactant: CC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Reaction time: 1.67 h

Procedure:
A solution of 2-fluoro-4-(3-hydroxy)propyl-1-triphenylmethylimidazole (386 mg. in dry pyridine (2 ml.) and acetyl chloride (78.5 μl.) was heated with stirring at 85° for 100 minutes. The solution was poured into water (25 ml.) and the mixture extracted with CH2Cl2 (3×15 ml.). The extract was washed with water and brine, dried (MgSO4), filtered, evaporated, and the residue azeotroped with toluene. The resulting orange oil was purified by column chromatography on silica gel eluting with CH2Cl2 /MeOH 100:0 to 98:2 v/v to give 4-(3-acetoxy)propyl-2-fluoro-1-triphenylmethylimidazole (127 mg.) having the following n.m.r. in CDCl3 : 1.9 (m, 2H); 2.02 (s, 3H); 2.47 (t, 2H); 4.07 (t, 2H) 6.22 (s, 1H); 7.0-7.5 (m, 15H).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[I:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:18]3[CH2:19][N:20]([C:23](=[O:25])[CH3:24])[CH2:21][CH2:22][C:17]=3[NH:16][N:15]=2)=[CH:10][CH:9]=1.[CH2:26]([CH:28]1[O:30][CH2:29]1)Cl>CN(C=O)C>[I:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:18]3[CH2:19][N:20]([C:23](=[O:25])[CH3:24])[CH2:21][CH2:22][C:17]=3[N:16]([CH2:26][CH:28]3[CH2:29][O:30]3)[N:15]=2)=[CH:12][CH:13]=1
Reactant: ClCC1CO1
Reactant: CC(=O)N1CCc2[nH]nc(-c3ccc(I)cc3)c2C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)N1CCc2c(c(-c3ccc(I)cc3)nn2CC2CO2)C1
Reaction time: 17 h
Yield: 57.6 %

Procedure:
Cs2CO3 (1.30 g, 4.01 mmol) was added to a solution of 1-[3-(4-iodo-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (1.34 g, 3.65 mmol) and epichlorohydrin (2.85 mL, 36.4 mmol) in DMF (10.0 mL). The mixture was stirred for 17 h then partitioned between EtOAc (400 mL) and saturated NaHCO3 (150 mL). The NaHCO3 layer was extracted with EtOAc (2×150 mL). The combined extracts were washed with H2O (2×150 mL), brine (150 mL), dried over Na2SO4 and concentrated. The residue was purified by column chromatography (silica, 10-25% acetone/CH2Cl2) to give 890 mg (58%) of the title compound. HPLC, tR=5.53 min. (Reverse phase conditions: HP 1100 LCMS, Phenomenex luna 2.1×150 mm column, 60% MeOH/H2O (0.5% AcOH) to 90% MeOH/H2O (0.5% AcOH), held at initial conditions for 2 min then ramped to final conditions over 5 min.) MS (electrospray), m/z calculated for C17H18IN3O2Na [M+Na]+ 445.04, found 445.95. 1H NMR (CDCl3, 500 MHz, a mixture of amide rotamers): 7.76 (d, J=8.3 Hz, 2H), 7.75 (d, J=8.3 Hz, 2H), 7.42 (d, J=8.2 Hz, 2H), 7.35 (d, J=8.2 Hz, 2H), 4.80 and 4.73 (A and B of AB quartet, Jab=15.6 Hz, 2H), 4.60 (s, 2H), 4.84 (dd, J=15.1, 2.1 Hz, 1H), 4.42 (dd, J=15.0, 2.1 Hz, 1H), 4.11 (t, J=5.0, Hz, 1H), 4.08 (t, J=5.0 Hz, 1H), 3.98-3.87 (m, 2H), 3.74 (m, 2H), 3.34 (m, 2H), 2.87-2.72 (m, 6H), 2.52 (dd, J=4.6, 2.6 Hz, 1H), 2.48 (dd, J=4.5, 2.6, 1H), 2.20 (s, 3H), 2.14 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[C:3]1[S:4][C:5]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:6]=2[N:7]=1.Br[CH:21]([CH3:26])[C:22]([O:24][CH3:25])=[O:23].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:1][N:2]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:21]([CH3:26])[C:22]([O:24][CH3:25])=[O:23])=[CH:15][CH:14]=1)[C:3]1[S:4][C:5]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:6]=2[N:7]=1
Reactant: CN(c1ccc(O)cc1)c1nc2cc(Cl)ccc2s1
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C)Oc1ccc(N(C)c2nc3cc(Cl)ccc3s2)cc1
Temperature: 100 °C
Yield: 59.8 %

Procedure:
A mixture of 4-[N-methyl-N-(5-chloro-2-benzothiazolyl)amino]phenol (2.0 g), methyl 2-bromopropionate (1.16 g), potassium carbonate (1.05 g) and dimethylformamide was heated at a temperature of 100° C. for a period of 1 hr with vigorous stirring. After cooling the mixture was poured into water and the aqueous mixture was extracted with dichloromethane. The organic extract was washed with water, dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure. The residue was recrystallised from methanol to give methyl 2-{4-[N-methyl-N-(5-chloro-2-benzothiazolyl)amino]phenoxy}propionate (1.55 g) as colourless crystals, mp 120° C.
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:13][N:14]([CH2:18][CH3:19])[C:15]([NH2:17])=[S:16])[CH:8]=2)[N:3]=1.[CH:20]([CH:22](Cl)[C:23]([O:25][CH2:26][CH3:27])=[O:24])=O>CN(C)C=O>[CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:13][N:14]([C:15]3[S:16][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:20][N:17]=3)[CH2:18][CH3:19])[CH:8]=2)[N:3]=1
Reactant: CCOC(=O)C(Cl)C=O
Reactant: CCN(Cc1ccc2nc(C)[nH]c(=O)c2c1)C(N)=S
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(N(CC)Cc2ccc3nc(C)[nH]c(=O)c3c2)s1
Temperature: 100 °C
Yield: 21.8 %

Procedure:
A mixture of the thiourea (4.67 g), ethyl formylchloroacetate (Archiv der Pharmazie, 1953, 286, 494; 2.55 g) and dimethylformamide (25 ml) was stirred and heated to 100° C. for 1 hour. The mixture was cooled, filtered and the filtrate was evaporated. The residue was partitioned between methylene chloride and a saturated aqueous sodium bicarbonate solution. The organic solution was dried over sodium sulphate, filtered and evaporated. The residue was purified by trituration in ethyl acetate to give ethyl 2-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-ethylamino]thiazole-5-carboxylate (1.37 g), m.p. 188°-192° C.