Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH2:53]([NH:59][CH2:60][C:61]1[CH:73]=[CH:72][C:64]2[O:65][C:66]([CH3:71])([CH3:70])[O:67][C:68](=[O:69])[C:63]=2[CH:62]=1)[CH2:54][CH2:55][CH2:56][CH2:57][CH3:58]>C(Cl)Cl>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([N:59]([CH2:60][C:61]3[CH:73]=[CH:72][C:64]4[O:65][C:66]([CH3:71])([CH3:70])[O:67][C:68](=[O:69])[C:63]=4[CH:62]=3)[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])=[O:19])=[CH:20][CH:21]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(C(=O)O)cc2)cc1
Reactant: CCCCCCNCc1ccc2c(c1)C(=O)OC(C)(C)O2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCN(Cc1ccc2c(c1)C(=O)OC(C)(C)O2)C(=O)c1ccc(C#Cc2ccc(CCCC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.4 %

Procedure:
A solution of 4-(4-butylphenylethynyl)benzoic acid (330 mg, 1.19 mmol), EDC.HCl (231 mg, 1.21 mmol), HOBT (163 mg, 1.21 mmol) and DIEA (256 μl, 1.51 mmol) in DCM (15 mL) was stirred 10 min at rt. Then a solution of 6-[(hexylamino)methyl]-2,2-dimethyl-4H-1,3-benzodioxin-4-one (293 mg, 1.01 mmol) in DCM (5 mL) was added and the resulting mixture was stirred 3 hrs at rt. The reaction mixture was diluted with DCM and washed with a saturated aqueous solution of NaHCO3, an aqueous solution of HCl (1N) and brine. Organic layer was dried over MgSO4 and the solvent was removed under reduced pressure. Purification by flash chromatography on silica gel (EtOAc/c-Hex (20/80)) gave 420 mg (73%) of the title compound. HPLC, Rt: 6.18 min (purity: 92.3%). A second purification by preparative HPLC with a X-Terra column allowed the isolation of the title compound (300 mg, 54% yield) as a white powder. HPLC, Rt: 6.15 min (purity: 99.1%). LC/MS, M+(ESI): 552.7. 1H NMR (CDCl3) δ: 0.82 (m, 3H), 0.91 (t, J=7.3 Hz, 3H), 1.09-1.41 (m, 8H), 1.53 (m, 4H), 1.72 (s, 6H), 2.60 (t, J=7.6 Hz, 2H), 3.16-3.45 (m, 2H), 4.50-4.70 (m, 2H), 6.96 (d, J=8.5 Hz, 1H), 7.15 (d, J=8.1 Hz, 2H), 7.37 (d, J=8.3 Hz, 2H), 7.42 (d, J=7.9 Hz, 2H), 7.52-7.84 (m, 4H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[N:12]([CH2:13][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])[C@H:11]([C:19]([F:22])([F:21])[F:20])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.Cl.[C@H:24]12[CH2:30][C@H:27]([NH:28][CH2:29]1)[CH2:26][O:25]2.C(N(CC)CC)C>C(OCC)(=O)C>[CH3:16][CH:15]([CH3:17])[C:14](=[O:18])[CH2:13][N:12]1[C:4]2=[N:3][C:2]([N:28]3[CH2:29][C@@H:24]4[CH2:30][C@H:27]3[CH2:26][O:25]4)=[CH:7][C:6](=[O:8])[N:5]2[CH2:9][CH2:10][C@H:11]1[C:19]([F:22])([F:21])[F:20]
Reactant: CC(C)C(=O)CN1c2nc(Cl)cc(=O)n2CC[C@H]1C(F)(F)F
Reactant: C1O[C@@H]2CN[C@H]1C2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)C(=O)CN1c2nc(N3C[C@@H]4C[C@H]3CO4)cc(=O)n2CC[C@H]1C(F)(F)F
Temperature: 130 °C
Yield: 49 %

Procedure:
220 mg (0.51 mmol) of (8S)-2-chloro-9-(3-methyl-2-oxobutyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 105.99 mg (0.78 mmol) of (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride are mixed together. The powder obtained is placed in a tube and 227 μl (1.63 mmol) of triethylamine are added. The tube is sealed and heated at 130° C. in an oil bath for 3 hours. The crude product obtained is taken up in ethyl acetate and the organic phase is washed with water, dried over magnesium sulfate and then evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 95/5 EtOAc/MeOH) to give 100 mg of (8S)-9-(3-methyl-2-oxobutyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, the characteristics of which are as follows:
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].[N:10]#[C:11]Br>CCOCC.CCCCCC>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][N:6]=[C:11]=[NH:10])[CH3:2]
Reactant: CCOC(CN)OCC
Reactant: N#CBr
Solvent: CCOCC
Solvent: CCCCCC
Product: CCOC(CN=C=N)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.6 %

Procedure:
A solution of the aminoacetaldehyde diethyl acetal (5.32 g, 40 mmol) in ether (20 mL) was added to a suspension of CNBr (4.22 g, 40 mmol) in hexane (20 mL) at RT. The reaction mixture was stirred at RT overnight. The solid was removed by filtration and washed with ether. The combined filtrate was concentrated. Flash chromatography of the concentrated residue afforded 2.82 g (45%) of the N-(2,2-diethoxyethyl)carbodiimide (a). 1H NMR (500 MHz, CDCl3): 4.58 (t, J=5.5 Hz, 1H), 3.85 (br s, 1H), 3.73 (m, 2H), 3.56 (m, 2H), 3.16 (J=5.5 Hz, 2H), 1.23 (t, J=7.0 Hz, 3H), MS: 156.8 (M−H)−; 180.9 (M+Na)+.
Reaction SMILES: CO[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[C:18]([F:20])[C:17]([O:21][CH3:22])=[CH:16][C:15]=3[CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:11][CH:12]=2)[N:7](C2CCCCO2)[N:6]=1)=[NH:4].C(OC([N:41]1[CH2:46][CH2:45][C:44](OCC)(OCC)[CH:43]([NH2:53])[CH2:42]1)=O)(C)(C)C.C(O)(=O)C.[ClH:58]>C(O)C>[ClH:58].[ClH:58].[ClH:58].[F:20][C:18]1[C:17]([O:21][CH3:22])=[CH:16][C:15]([CH2:23][C:24]([F:27])([F:26])[F:25])=[C:14]([C:10]2[CH:9]=[C:8]3[C:13]([C:5]([C:3]4[NH:53][C:43]5[CH2:42][NH:41][CH2:46][CH2:45][C:44]=5[N:4]=4)=[N:6][NH:7]3)=[CH:12][CH:11]=2)[CH:19]=1
Reactant: CCOC1(OCC)CCN(C(=O)OC(C)(C)C)CC1N
Reactant: COC(=N)c1nn(C2CCCCO2)c2cc(-c3cc(F)c(OC)cc3CC(F)(F)F)ccc12
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: COc1cc(CC(F)(F)F)c(-c2ccc3c(-c4nc5c([nH]4)CNCC5)n[nH]c3c2)cc1F
Temperature: 50 °C
Yield: 96.8 %

Procedure:
To a solution of 6-[5-fluoro-4-methoxy-2-(2,2,2-trifluoro-ethyl)-phenyl]-1-(tetrahydro-pyran-2-yl)-1H-indazole-3-carboximidic acid methyl ester (Preparation 37, 1.64 g, 3.78 mmol) in ethanol (5 mL) was added a solution of 3-amino-4,4-diethoxy-piperidine-1-carboxylic acid tert-butyl ester (US-2004/0229862, 1.15 g, 3.97 mmol) in ethanol (7.5 mL). Acetic acid (430 μL, 7.56 mmol) was added and the reaction mixture was heated at 50° C. for 18 hours and then concentrated in vacuo to give a brown oil. The oil was dissolved in ethanol (15 mL) and the resulting solution was treated with concentrated hydrochloric acid (12M, 4.75 mL, 56.7 mmol) and then heated at 80° C. for 18 hours. The solvent was removed in vacuo to yield the title compound (2.03 g) in a 97% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([SH:12])[N:11]=[C:4]2[N:3]=1.Br[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][CH2:15][CH2:14][S:12][C:10]2[N:11]=[C:4]3[N:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]3[N:9]=2)=[CH:18][CH:19]=1
Reactant: Clc1ccc(OCCBr)cc1
Reactant: Cc1cc(C)n2nc(S)nc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)n2nc(SCCOc3ccc(Cl)cc3)nc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.7 %

Procedure:
A mixture of 5,7-dimethyl-[1,2,4]-triazolo[1,5-a]pyrimidine-2-thiol (1.0 g, 5.6 mmol), 1-(2-bromoethoxy)-4-chlorobenzene (1.19 g, 5.1 mmol), potassium carbonate (1.75 g, 12.6 mmol), and anhydrous N,N-dimethylformamide (6 mL) was added to a 20 mL scintillation vial with a magnetic stirring bar. The vial was capped loosely and the mixture allowed to stir at room temperature for 30 minutes. Progress of the reaction was monitored by analytical HPLC with UV detection (Rt=8.28 min). The mixture contained solids starting at 30 minutes and was stopped stirring at 1 hour. The mixture was transferred into an Erlenmeyer flask with a total of 70 mL of water, and allowed to stir for 10 min. The resulting solid was isolated by filtration, rinsed with 100 mL of water, and allowed to dry under reduced pressure. The off-white powder was >90% pure by analytical HPLC with UV detection at 215 nm. The solid was dissolved in 25 mL of ethanol with gentle warming, diluted with 5 mL of water and allowed to cool. The fine white needles that formed were isolated by filtration, washed with 20 mL of cold ethanol, and dried to afford the title compound (1.43 g, 85% yield). EM (calc.): 334.1; MS (ESI) m/e: 335.1 (M+H)+. 1H NMR (DMSO-d6, 400 MHz) δ ppm: 7.31 (d, 2H), 7.12 (s, 1H), 7.03 (d, 2H), 4.33 (t, 2H), 3.60 (t, 2H), 2.68 (s, 3H), 2.55 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4]/[N:5]=[CH:6]/[CH:7]=[CH:8]/[C@H:9]1[CH2:14][CH2:13][C@:12]2([OH:29])[C@H:15]3[C@H:25]([CH2:26][CH2:27][C@:10]12[CH3:11])[C@:23]1([CH3:24])[C@@H:18]([CH2:19][C@@H:20]([OH:28])[CH2:21][CH2:22]1)[CH2:17][CH2:16]3.[N+]([O-])(O)=O.[C:34](N1C(C)=CC(C)=N1)(=[NH:36])[NH2:35]>C(O)C>[NH:1]([CH2:2][CH2:3][O:4][N:5]=[CH:6]/[CH:7]=[CH:8]/[C@H:9]1[CH2:14][CH2:13][C@:12]2([OH:29])[C@H:15]3[C@H:25]([CH2:26][CH2:27][C@:10]12[CH3:11])[C@:23]1([CH3:24])[C@@H:18]([CH2:19][C@@H:20]([OH:28])[CH2:21][CH2:22]1)[CH2:17][CH2:16]3)[C:34]([NH2:36])=[NH:35]
Reactant: Cc1cc(C)n(C(=N)N)n1
Reactant: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](/C=C/C=N/OCCN)CC[C@]12O
Solvent: O=[N+]([O-])O
Solvent: CCO
Product: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](/C=C/C=NOCCNC(=N)N)CC[C@]12O
Yield: 58.9 %

Procedure:
A solution of 1.00 g of (E,E)-17β-[3-(2-aminoethoxyimino)-1-propenyl]-5β-androstane-3β,14β-diol (I-ao) and 1.05 g of 1-amidino-3,5-dimethylpyrazole nitrate in 20 ml of ethanol was heated at reflux for 10 hrs. The solution was evaporated to dryness under reduced pressure and the crude product was ground with water and then with diethyl ether/ethanol to give 0.65 g of the title compound (I-as), as a nitrate, white solid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:10]2=[O:31])=[C:4]([OH:32])[CH:3]=1.[C:33]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[C:19]1([CH:18]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]3([C:5]4[CH:6]=[C:7]([F:8])[C:2]([F:1])=[CH:3][C:4]=4[O:32][CH2:33]3)[C:10]2=[O:31])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1C(c2cc(F)c(F)cc2O)c2ccccc2N1C(c1ccccc1)c1ccccc1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1cc(F)c(F)cc12

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 3-(4,5-difluoro-2-hydroxyphenyl)-1-(diphenylmethyl)-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1′-(diphenylmethyl)-5,6-difluorospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (70%) as a colorless solid: mp 213-216° C.; 1H NMR (300 MHz, CDCl3) δ 7.41-7.26 (m, 10H), 7.15-7.12 (m, 1H), 7.08-6.97 (m, 3H), 6.78 (dd, J=10.5, 6.3 Hz, 1H), 6.54 (d, J=8.4 Hz, 1H), 6.44 (dd, J=9.0, 7.8 Hz, 1H), 5.03 (d, J=9.0 Hz, 1H), 4.77 (d, J=9.3 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 176.8, 156.6 (d, J=11.0 Hz), 151.2 (dd, JC-F=248.2, 14.5 Hz), 145.6 (dd, JC-F=241.5, 13.9 Hz), 141.7, 137.4, 137.1, 131.5, 128.8, 128.8, 128.7, 128.3, 128.3, 128.1, 128.0, 124.2 (dd, J=6.4, 3.3 Hz), 123.8, 123.3, 112.4, 111.5 (dd, J=20.4, 1.6 Hz), 100.1 (d, J=22.4), 80.8, 58.9, 57.5; MS (ES+) m/z 440.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[S:24])[O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:34].O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[S:24])[O:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:32][C:33](=[O:34])[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:21][CH:22]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(CBr)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=S)OCc2ccc(O)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(=S)OCc2ccc(OCC(=O)c3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.9 %

Procedure:
a mixture of 4-hydroxybenzyl 4-tert-butoxycarbonylpiperazine-1-thiocarboxylate (100 mg, 0.28 mmol), cesium carbonate (140 mg, 1.5 eq) and α-bromoacetophenone (84 mg, 1.5 eq) in DMF was shaken at ambient temperature for 16 h. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (3×20 mL). The organic extracts were washed with water (30 mL), dried (MgSO4) and condensed to give the desired product (129 mg, 96%) as a yellow oil: NMR δH(400 MHz; d6-DMSO) 1.40 (9H, s), 3.30–3.36 (4H, m), 3.43 (4H, br s), 4.07 (2H, s), 5.54 (2H, s), 6.86–6.91 (2H, m), 7.20–7.26 (2H, m), 7.54–7.60 (2H, m) and 7.66–7.72 (1H, m); HPLC (XTERRA, 50/80, 220 nm) 96.1% (6.56 min).
Reaction SMILES: C(OC(=O)[CH:5]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([CH2:28][CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23](=[O:27])[N:24]([CH3:26])[CH3:25])[CH:18]=2)=[O:15])=[N:10][CH:9]=1)[CH3:6])C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(C[C:50]([OH:52])=[O:51])N=2)CCCC1.C1(CNC2C=C(C=CC=2)C(N(C)C)=O)CCCC1.C(OC(=O)C(SC1SC(N)=NC=1)C)C>>[CH:29]1([CH2:28][N:16]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23](=[O:27])[N:24]([CH3:26])[CH3:25])[CH:18]=2)[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][CH2:5][CH2:6][C:50]([OH:52])=[O:51])=[CH:9][N:10]=2)[CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Reactant: CCOC(=O)C(C)Sc1cnc(NC(=O)N(CC2CCCC2)c2cccc(C(=O)N(C)C)c2)s1
Agent: CCOC(=O)C(C)Sc1cnc(N)s1
Agent: CN(C)C(=O)c1cccc(NCC2CCCC2)c1
Product: CN(C)C(=O)c1cccc(N(CC2CCCC2)C(=O)Nc2ncc(SCCC(=O)O)s2)c1

Procedure:
The title compound was prepared via {2-[3-cyclopentylmethyl-3-(3-dimethylcarbamoyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-propionic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using 3-(cyclopentylmethyl-amino)-N,N-dimethyl-benzamide and (2-amino-thiazol-5-ylsulfanyl) propionic acid ethyl ester
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:14]([Li])CCC.S(OC)(OC)(=O)=O.[Cl-].[NH4+]>C1COCC1>[CH3:14][C:4]1[C:5]2[O:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[C:9]=2[CH:1]=[CH:2][CH:3]=1
Reactant: c1ccc2c(c1)oc1ccccc12
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: COS(=O)(=O)OC
Product: Cc1cccc2c1oc1ccccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.2 %

Procedure:
Dibenzofuran (26.94 g, 160 mmol) was dissolved in dry THF (500 ml) and cooled to -78° C. n-Butyl lithium (1.6M in hexane, 200 ml, 320 mmol) was added in portions over 30 mins. and the solution was allowed to warm to room temperature over 2.5 hours. The solution was recooled to -70° C. and a mixture of dimethyl sulphate (32 ml, 340 mmol) in dry THF (100 ml) was added dropwise. Once the addition was complete, the reaction was allowed to warm to room temperature, stirred for 18 hours and poured onto saturated ammonium chloride solution (400 ml). The phases were separated and the aqueous extracted twice with ether. The combined organic phases were dried (MgSO4) and evaporated in vacuo. Chromatography on silica (eluting with 40-60 petrol) gave the pure product as a clear oil (29.2 g, 100%) δH [2H6 ]-DMSO 8.1 (1H, d), 7.9 (1H, d), 7.7 (1H, d),7.5 (1H, t), 7.4 (1H, t), 7.25 (2H, m), 2.55 (3H, s).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:19]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:18]=[N:17][N:16]=2)=[CH:5][CH:4]=1.[CH2:39]([NH2:44])[CH2:40][CH2:41][CH2:42][CH3:43].C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH2:39]([NH:44][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:19]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:18]=[N:17][N:16]=2)=[CH:5][CH:4]=1)[CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: CCCCCN
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCNCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
A mixture of 10.0 g (16.5 mmole) of 5-[4'-(bromomethyl)biphenyl-2-yl]-N-trityltetrazole [P. E. Aldrich, M. E. Pierce, and J. J. V. Duncia, European Patent Application 291,969 (1988)], 9.5 mL (7.14 g, 8.2 mmole) of n-pentylamine, 2.8 mL (2.03 g, 20 mmole) of triethylamine, and 100 mL of dry methylene chloride was stirred under N2 at room temperature overnight. Next, the mixture was shaken with 100 mL of 0.25M citric acid (aqueous). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The viscous oil was flash chromatographed on silica gel (elution initially with 1:1 hexane-EtOAc and then with a larger volume of EtOAc alone) to yield 4.57 g (49%) of the title compound as a very viscous oil, homogeneous by TLC (EtOAc); FAB-MS m/e 563 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.[C:42]([O:46][C:47](=[O:62])[NH:48][C:49]1[CH:54]=[CH:53][CH:52]=[C:51](CN2C=CC(N)=N2)[CH:50]=1)([CH3:45])([CH3:44])[CH3:43]>C(Cl)Cl>[C:42]([O:46][C:47](=[O:62])[NH:48][C:49]1[CH:50]=[CH:51][CH:52]=[C:53]([CH2:21][N:18]2[CH:19]=[CH:20][C:16]([NH:15][C:13](=[O:14])[C@@H:12]([C:4]3[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[C:2]([Cl:1])[CH:3]=3)[CH2:22][CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)=[N:17]2)[CH:54]=1)([CH3:45])([CH3:43])[CH3:44]
Reactant: CC(C)(C)OC(=O)Nc1cccc(Cn2ccc(N)n2)c1
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cccc(Cn2ccc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)n2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59 %

Procedure:
2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 500 mg, 1.52 mmol) was suspended in methylene chloride (7.6 mL) and a 2.0 M solution of oxalyl chloride in methylene chloride (760 μL, 1.52 mmol) was added and the reaction stirred at 25° C. for 10 min. The solution was chilled to 0° C. and 2,6-lutidine (354 μL, 3.04 mmol) was added. The reaction continued to stir at 0° C. for 15 min. [3-(3-Amino-pyrazol-1-ylmethyl)-phenyl]-carbamic acid tert-butyl ester (437 mg, 1.52 mmol) was dissolved in methylene chloride (7 mL) and added dropwise to the reaction. The ice bath was removed and the reaction continued to stir at 25° C. for 30 min. The reaction was diluted with ethyl acetate (300 mL), washed with water (2×50 mL), saturated aqueous brine solution (20 mL), dried over magnesium sulfate and concentrated in vacuo to a yellow foam. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 120 g; 5% ethyl acetate/methylene chloride to 15% ethyl acetate/methylene chloride) afforded (3-{3-[2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-phenyl)-carbamic acid tert-butyl ester (539 mg 59%) as a pale pink powder: ESI-LRMS m/e calcd for C30H37ClN4O5S [M+] 600.22, found 601.50 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.03-1.23 (m, 2H, CH2), 1.45-1.93 (m, 8H, 4×CH2), 1.51 (s, 9H, 3×CH3), 2.15-2.30 (m, 1H, CH), 3.26 (s, 3H, SO2CH3), 3.54 (t, J=7.8 Hz, 1H, CH), 5.11 (s, 2H, NCH2), 6.49 (brs, 1H, NH), 6.71 (d, J=2.5 Hz, 1H, Ar), 6.82 (m, 1H, Ar), 7.19-7.25 (m, 2H, Ar), 7.26-7.29 (brs, 1H, Ar), 7.31 (d, J=2.5 Hz, 1H, Ar), 7.45 (dd, Jo=8.2, Jm=1.6 Hz, 1H, Ar), 7.59 (d, Jm=1.6 Hz, 1H, Ar), 8.08 (d, Jo=8.2 Hz. 1H, Ar), 8.17 (brs, 1H, NH).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([C:14]2[CH:18]=[C:17]([CH2:19][CH2:20][CH:21]=O)[O:16][N:15]=2)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:23]([N:30]1[CH2:35][CH2:34][N:33]([CH2:21][CH2:20][CH2:19][C:17]2[O:16][N:15]=[C:14]([C:10]3[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:9]=3)[CH:18]=2)[CH2:32][CH2:31]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=CCCc1cc(-c2cccc(Oc3ccccc3)c2)no1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: c1ccc(CN2CCN(CCCc3cc(-c4cccc(Oc5ccccc5)c4)no3)CC2)cc1
Yield: 95.1 %

Procedure:
About 2 min after dissolving 3-[3-(3-phenoxypheny)isoxazol-5-yl]propanal (20 mg, 0.07 mmol) and 1-benylpiperazine (11.9, 0.07 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (43 mg, 0.20 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 4.5 hr and followed the same processes as in Example 1 to obtain 30.2 mg (97.6%) of the target compound.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:3]([NH:5][C:6]1[N:10]([CH3:11])[N:9]=[C:8]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([Cl:18])[CH:13]=2)[CH:7]=1)=[O:4].CCN(C(C)C)C(C)C.Br[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38]>CN(C=O)C>[Cl:18][C:14]1[CH:13]=[C:12]([C:8]2[CH:7]=[C:6]([NH:5][C:3](=[O:4])[C@@H:2]([NH:1][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:10]([CH3:11])[N:9]=2)[CH:17]=[CH:16][N:15]=1
Reactant: Cn1nc(-c2ccnc(Cl)c2)cc1NC(=O)[C@@H](N)Cc1ccccc1
Reactant: CCOC(=O)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CN[C@@H](Cc1ccccc1)C(=O)Nc1cc(-c2ccnc(Cl)c2)nn1C
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a 1000 ml flask was added 8.6 g of (2S)-2-amino-N-(3-(2-chloropyridin-4-yl)-1-methyl-1H-pyrazol-5-yl)-3-phenylpropanamide 1.E, 100 ml of DMF, 6.0 ml of DIEA and the reaction was cooled to 0° C. To the reaction was then added 2.8 ml of ethyl bromoacetate and the reaction was stirred at 22° C. for 16 hours at which time the crude was partitioned between 1500 ml EtAc, 2×400 ml of saturated brine, and 2×400 ml of water (Note: no product observed in aqueous layer). The organic solvent was removed by rotary evaporation and the crude purified with a silica gel column (eluting with 30% EtAc in Hexane) to give 6.3 g of ethyl 2-((S)-1-(3-(2-chloropyridin-4-yl)-1-methyl-1H-pyrazol-5-ylamino)-1-oxo-3-phenylpropan-2-ylamino)acetate 17.7.F as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].C(Cl)(=O)C(Cl)=O.C[N:21](C=O)C.[NH4+].[OH-]>C(Cl)Cl.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([NH2:21])=[O:8]
Reactant: O=C(O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: NC(=O)c1cc(F)ccc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 88 %

Procedure:
To 5-Fluoro-2-nitro-benzoic acid (3 g, 16,2 mmol) in 200 mL of methylene chloride was added oxalyl chloride (2.26 g, 17.8 mmol) and a drop of DMF. After stirring for 2 h, the solution was poured into concentrated NH4OH. The partial solution was poured into water, extracted with Ethyl acetate, dried (Na2SO4) and concentrated to give 5-Fluoro-2-nitro-benzamide (2.61 g, 88% yield) used without purification. LCMS m/e 185.1(M+H) 183.2 (M−H), HPLC tr=2,9 min (100%).