Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][NH:17][S:18]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:20])=[O:19])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[H-].[Na+].FC(F)(F)S(O[CH2:36][C:37]([F:40])([F:39])[F:38])(=O)=O.O>CN(C)C(=O)C>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][N:17]([CH2:36][C:37]([F:40])([F:39])[F:38])[S:18]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:20])=[O:19])=[CH:14][CH:15]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CC(=O)N1CCN(c2ccc(CNS(=O)(=O)Cc3ccccc3)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(=O)N1CCN(c2ccc(CN(CC(F)(F)F)S(=O)(=O)Cc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
To a solution of N-[[4-(4-acetylpiperazin-1-yl)phenyl]methyl]-1-phenyl-methanesulfonamide (100 mg, 0.25 mmol) in N,N-dimethylacetamide (3 mL) was added sodium hydride (60% in mineral oil) (11.3 mg, 0.28 mmol) and stirred at ambient temperature for 30 minutes. 2,2,2-Trifluoroethyl trifluoromethanesulfonate (72 mg, 0.31 mmol) was then added and stirred at ambient temperature for 16 hours. Water was added and the reaction was partitioned between water and dichloromethane. The dichloromethane layer was isolated with a phase separator cartridge and concentrated and purified by preparative reverse phase HPLC to yield 47 mg of N-(4-(4-acetylpiperazin-1-yl)benzyl)-1-phenyl-N-(2,2,2-trifluoroethyl)methanesulfonamide. 1H NMR (400 MHz, DMSO) δ 7.47-7.32 (m, 5H), 7.21 (d, J=8.5 Hz, 2H), 6.95 (d, J=8.5 Hz, 2H), 4.52 (s, 2H), 4.27 (s, 2H), 3.83 (q, J=9.3 Hz, 2H), 3.62-3.51 (m, 4H), 3.22-3.13 (m, 2H), 3.13-3.03 (m, 2H), 2.03 (s, 3H); LCMS (m/z) ES+ 470.1 [M+1]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14]([CH3:16])=[CH2:15])[C:6]1=[O:17].CC([N:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[C:22]1=[O:36])C.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CC(C)CC(=O)C>[O:36]=[C:22]1[N:23]([CH2:30][CH2:31][CH2:32][N:33]2[CH2:34][CH2:35][CH:4]([N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[N:7]([CH:14]([CH3:16])[CH3:15])[C:6]3=[O:17])[CH2:3][CH2:2]2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[NH:21]1
Reactant: CC(C)n1c(=O)n(C2CCNCC2)c2ccccc21
Reactant: C=C(C)n1c(=O)n(CCCCl)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: CC(C)n1c(=O)n(C2CCN(CCCn3c(=O)[nH]c4ccccc43)CC2)c2ccccc21
Temperature: 25 °C
Yield: 64 %

Procedure:
A mixture of 4.15 parts of 1-(3-chloropropyl)-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one, 3.9 parts of 1-(1-methylethyl)-3-(4-piperidinyl)-2H-benzimidazol-2-one, 3.2 parts of sodium carbonate, 0.1 parts of potassium iodide and 120 parts of 4-methyl-2-pentanone is stirred and refluxed overnight. The reaction mixture is cooled to room temperature, water is added and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is stirred for 30 minutes with a solution of 12 parts of a concentrated hydrochloric acid solution in 40 parts of ethanol. The solvent is evaporated and the residue is suspended in water. The suspension is alkalized with a diluted ammonium hydroxide solution and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 4-methyl-2-pentanone. The product is filtered off and dried, yielding 4.2 parts (64%) of 1-{1-[3-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)propyl]-4-piperidinyl}-1,3-dihydro-3-(1-methylethyl)-2H-benzimidazol-2-one; mp. 174.3° C.
Reaction SMILES: [CH3:1][CH:2]1[O:7][C:6]2[CH:8]=[CH:9][C:10]([O:12][CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:11][C:5]=2[NH:4][C:3]1=[O:19].C([O-])([O-])=O.[K+].[K+].F[C:27]1[CH:36]=[CH:35][C:30]([C:31]([NH:33][CH3:34])=[O:32])=[CH:29][CH:28]=1>CS(C)=O>[CH3:34][NH:33][C:31](=[O:32])[C:30]1[CH:35]=[CH:36][C:27]([N:16]2[CH2:17][CH2:18][CH:13]([O:12][C:10]3[CH:9]=[CH:8][C:6]4[O:7][CH:2]([CH3:1])[C:3](=[O:19])[NH:4][C:5]=4[CH:11]=3)[CH2:14][CH2:15]2)=[CH:28][CH:29]=1
Reactant: CC1Oc2ccc(OC3CCNCC3)cc2NC1=O
Reactant: CNC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CNC(=O)c1ccc(N2CCC(Oc3ccc4c(c3)NC(=O)C(C)O4)CC2)cc1
Temperature: 120 °C
Reaction time: 72 h
Yield: 22.8 %

Procedure:
In a 4 mL screw cap vial, 2-methyl-6-(piperidin-4-yloxy)-2H-benzo[b][1,4]oxazin-3(4H)-one 394E (0.054 g, 0.206 mmol), K2CO3 (0.142 g, 1.029 mmol), and 4-fluoro-N-methylbenzamide (0.038 g, 0.247 mmol) were suspended in DMSO (0.412 mL) to give a brown suspension. The reaction was stirred at 120° C. for 72 hr. The crude material was purified by prep HPLC-MS (40-75% MeCN in water). The fractions were collected and concentrated in vacuo affording the product as a tan solid (0.0186 g, 22.85% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.34-1.47 (m, 3H) 1.59-1.74 (m, 2H) 1.93-2.07 (m, 2H) 2.71-2.82 (m, 3H) 3.09-3.23 (m, 2H) 3.61 (br. s., 2H) 4.38-4.50 (m, 1H) 4.58 (q, J=6.65 Hz, 1H) 4.68 (d, J=6.57 Hz, 1H) 6.50 (d, J=2.78 Hz, 1H) 6.53-6.62 (m, 1H) 6.67 (dd, J=8.72, 2.91 Hz, 1H) 6.88 (d, J=8.84 Hz, 1H) 6.94-7.06 (m, 2H) 7.71 (d, J=8.84 Hz, 2H) 7.81-7.88 (m, 1H) 8.10-8.20 (m, 1H) 10.57 (s, 1H). ESI-MS: m/z 396.3 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1>>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([C:2]2[S:1][CH:5]=[CH:4][N:3]=2)=[CH:8][CH:9]=1
Reactant: c1cscn1
Reactant: COc1ccc(Br)cc1
Product: COc1ccc(-c2nccs2)cc1
Yield: 67 %

Procedure:
The title compound was prepared from thiazole (2.0 g, 24 mmol) and 4-bromoanisole (3.0 g, 16 mmol) using the procedure of Example 146, step 1 with 67% yield (2.0 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:9]3[CH:18]=[C:19]([CH:22]([CH3:24])[CH3:23])[CH:20]=[CH:21][C:8]=3[S:7][C:6]=2[CH:25]=1.[F:26][C:27]1[CH:37]=[CH:36][C:30]([O:31][CH2:32][C:33](Cl)=O)=[CH:29][CH:28]=1>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH:10]([N:12]3[CH2:13][CH2:14][N:15]([CH2:33][CH2:32][O:31][C:30]4[CH:36]=[CH:37][C:27]([F:26])=[CH:28][CH:29]=4)[CH2:16][CH2:17]3)[C:9]3[CH:18]=[C:19]([CH:22]([CH3:23])[CH3:24])[CH:20]=[CH:21][C:8]=3[S:7][C:6]=2[CH:25]=1
Reactant: CC(C)c1ccc2c(c1)C(N1CCNCC1)Cc1ccc(F)cc1S2
Reactant: O=C(Cl)COc1ccc(F)cc1
Solvent: ClC(Cl)Cl
Product: CC(C)c1ccc2c(c1)C(N1CCN(CCOc3ccc(F)cc3)CC1)Cc1ccc(F)cc1S2
Reaction time: 12 h

Procedure:
A solution of 2.6 g of 3-fluoro-8-isopropyl-10-piperazino-10,11-dihydrodibenzo(b,f)thiepin in 15 ml of chloroform was stirred and treated dropwise with 1.7 g of 4-fluorophenoxyacetyl chloride and the mixture allowed to stand for 12 hours. It was then diluted with chloroform, washed with a 5% sodium hydroxide solution and water, dried with potassium carbonate, filtered and evaporated. The oily residue (3.7 g, 100%) was the crude 3-fluoro-10-[4-(4-fluorophenoxyacetyl)-piperazino]-8-isopropyl-10,11-dihydrodibenzo(b,f)thiepin which was used in this state for further work.
Reaction SMILES: [OH:1][CH:2]([CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6]CC)=[O:5].[OH-].[Na+]>CO.O>[OH:1][CH:2]([CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CCCC(O)CC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCC(O)CC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
The racemic ethyl 3-hydroxyhexanoate 3.46 g (21.6 mmol) obtained in Reference example 1 was dissolved in methanol 24 ml, sodium hydroxide 0.95 g in water 24 ml was added dropwise with cooling, and the mixture was reacted with stirring in a stream of nitrogen at room temperature for two hours. Methanol was removed from the reactant under reduced pressure, and the residue was neutralized with 1N-HCl. After saturating the resultant by adding sodium chloride, the solution was extracted with ethyl acetate, the extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to obtain racemic 3-hydroxyhexanoic acid 2.50 g (18.9 mmol, 87%). The resultant, benzyl bromide 6.47 g (37.8 mmol). sodium bicarbonate 3,81 g (45.4 mmol) and N,N-dimethylformamide 20 ml were reacted with stirring at room temperature for 27 hours in a stream of nitrogen. The reaction mixture was extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate and filtered, and the solvent was distilled off under reduced pressure. The residue was chromatographed with silica gel column to obtain racemic benzyl 3-hydroxyhexanoate 2.11 g (9.5 mmol, 50%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH:10]([C:12]1[N:13]=[CH:14][NH:15][CH:16]=1)=O.[BH4-].[Na+].O>CO>[Cl:1][C:2]1[C:3]([F:9])=[C:4]([NH:5][CH2:10][C:12]2[NH:13][CH:14]=[N:15][CH:16]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Cl)c1F
Reactant: O=Cc1c[nH]cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Fc1c(Cl)cccc1NCc1cnc[nH]1
Temperature: 60 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
To a solution of 3-chloro-2-fluoroaniline (0.44 g, 3 mmol) in methanol (5 ml) was added 4-formylimidazole (0.29 g, 3 mmol). After stirring the mixture overnight at 60° C. the solution was cooled and sodium borohydride (0.57 g, 15 mmol) was added. The reaction mixture was stirred at room temperature for 4 hours. Then water was added and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water, dried over magnesium sulfate and evaporated. The residue was purified by column filtration (heptane/ethyl acetate=1:1) to yield a light yellow liquid (0.55 mg, 81%); MS (ISP): 226.3 ((M+H)+.).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][NH:11][CH2:10][CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1>ClCCl>[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([N:11]2[CH2:10][CH2:9][NH:8][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:12]2)=[O:19])=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: c1ccc(C2CNCCN2)cc1
Solvent: ClCCl
Product: O=C(c1ccc(Br)cc1)N1CCNC(c2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
This compound could be made in the following manner: 500 mg of 2-phenylpiperazine would be dissolved in dichloromethane and cooled to 0° C. A solution of 0.5 equiv. of 4-bromobenzoyl chloride in dichloromethane would be added dropwise over 1 h at 0° C. The reaction would be stirred at 0° C. for 0.5 h, then allowed to warm to room temperature and stirred for a further 3 h until complete conversion. The reaction mixture would be diluted with dichloromethane, washed with 1M aqueous sodium hydroxide solution and brine, then dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue would be purified by column chromatography to afford (4-bromo-phenyl)-(3-phenyl-piperazin-1-yl)-methanone.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)O.[NH:9]1[CH2:14][CH2:13][S:12][CH2:11][CH2:10]1>[Cu]Cl>[S:12]1[CH2:13][CH2:14][N:9]([C:1]2[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=2)[CH2:10][CH2:11]1
Reactant: C1CSCCN1
Reactant: Oc1ccc(O)cc1
Agent: Cl[Cu]
Product: Oc1ccc(N2CCSCC2)cc1

Procedure:
(aa) A mixture of 99 g of hydroquinone, 13.5 g of copper(I) chloride and 180 ml of thiomorpholine is heated to boiling under reflux under argon for 47 hours. After cooling, the mixture is partitioned between 1N sodium hydroxide solution and dichloromethane, the sodium hydroxide extract is adjusted to about pH 1 with concentrated hydrochloric acid while cooling with ice and then partitioned between 0.1N hydrochloric acid and dichloromethane which contains 10% alcohol. The acidic extracts are adjusted to about pH 6 with 50 percent sodium hydroxide solution while cooling with ice and thereafter extracted in each case three times with dichloromethane which contains 10% alcohol as well as dichloromethane which contains 20% alcohol. The material obtained is distilled in a bulb-tube at 180° and 0.01 Torr and then recrystallized from methanol/ether. p-(Tetra-hydro-4H-1,4-thiazin-4-yl)phenol of melting point 156°-158° is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH2:7][NH:8][S:9]([C:12]2[C:20]3[N:19]=[N:18][NH:17][C:16]=3[CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1.[ClH:23].[N:24](OCCCCC)=O>C(O)C>[ClH:23].[NH:17]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([S:9]([NH:8][CH2:7][CH2:6][C:5]3[CH:21]=[CH:22][C:2]([NH:1][NH2:24])=[CH:3][CH:4]=3)(=[O:11])=[O:10])[C:20]=2[N:19]=[N:18]1
Reactant: CCCCCON=O
Reactant: Nc1ccc(CCNS(=O)(=O)c2cccc3[nH]nnc23)cc1
Agent: Cl
Solvent: CCO
Product: NNc1ccc(CCNS(=O)(=O)c2cccc3[nH]nnc23)cc1
Reaction time: 2 h

Procedure:
N-(4-Aminophenethyl)benzotriazole-4-sulphonamide (4.53 g, 14 mM) was dissolved in a minimum of boiling ethanol (100 ml). The solution was cooled to -5°, saturated with dry hydrogen chloride and, after further cooling to -10°, amyl nitrite (1.84 g, 16 mM, 2.11 ml) was added over 10 minutes. The mixture was then stirred for 2 hours at -10°. The very small quantity of solid which remained was removed from the reaction mixture by filtration and the filtrate was added, all at once, to a solution of anhydrous stannous chloride (8.13 g, 43 mM) in ethanolic hydrogen chloride (10 ml) at 0°. The reaction mixture was stirred at 0° for 1 hour, left at 5° overnight and then poured into ether (1 liter). The solid which precipitated was collected (4.1 g).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:13]([CH3:15])[CH3:14])=[O:11])[C:7]2[CH:23]=[CH:24][CH:25]=[CH:26][C:6]=2[N:5]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:4](=[O:33])[CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:45][C:46]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[N:48]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[N:47]=1.CCOCC.CCOC(C)=O>CN(C=O)C.C1(C)C=CC=CC=1>[C:58]([O:57][C:55]([N:48]1[C:49]2[C:54](=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:46]([CH2:45][CH:3]2[C:2](=[O:1])[N:8]([CH2:9][C:10]([N:12]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]([CH3:15])[CH3:14])=[O:11])[C:7]3[CH:23]=[CH:24][CH:25]=[CH:26][C:6]=3[N:5]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:4]2=[O:33])=[N:47]1)=[O:56])([CH3:61])([CH3:60])[CH3:59]
Reactant: CC(C)N(C(=O)CN1C(=O)CC(=O)N(c2ccccc2)c2ccccc21)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2ccccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)N(C(=O)CN1C(=O)C(Cc2nn(C(=O)OC(C)(C)C)c3ccccc23)C(=O)N(c2ccccc2)c2ccccc21)c1ccc(F)cc1
Reaction time: 0.08 h
Yield: 117.6 %

Procedure:
To a stirring solution of 500 mg (1.12 mmol) of 2-(2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-(4-fluoro-phenyl)-N-isopropyl-acetamide, prepared as in Part B, in 10 mL DMF at 0° C. is added 2.68 mL (1.34 mmol, 1.2 equiv) of NaN(TMS)2 in toluene. The resulting solution is stirred 5 min, and 417 mg (1.34 mmol, 1.2 equiv) of 3-bromomethyl-1-tert-butoxycarbonyl-1H-indazole is added. The resulting solution is stirred 4.5 h, poured into 100 mL Et2O/EtOAc (1:1), washed with H2O (2×50 mL). The organic layer is separated, dried (MgSO4), and the solvents removed in vacuo to afford 890 mg of the crude title compound: low resolution MS (FAB) m/e 676 (MH+).
Reaction SMILES: N1C(C)=CC=CC=1C.[O:9]([S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])S(C(F)(F)F)(=O)=O.[F:24][C:25]([F:30])([F:29])[CH2:26][CH2:27]O>C(Cl)Cl>[F:23][C:20]([F:21])([F:22])[S:17]([O:9][CH2:27][CH2:26][C:25]([F:30])([F:29])[F:24])(=[O:18])=[O:19]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: OCCC(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: O=S(=O)(OCCC(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a cold (−25° C.), stirred solution of 2,6-lutidine (18.38 mL, 158 mmol) in DCM (120 mL) was added Tf2O (24.88 mL, 147 mmol) over 3 min, and the mixture was stirred for 5 min. To the reaction mixture was added 3,3,3-trifluoropropan-1-ol (12 g, 105 mmol) over an interval of 3 min. After 2 hr, the reaction mixture was warmed to room temperature and stirred for 1 hr. The reaction mixture was concentrated to half its volume, then purified by loading directly on a silica gel column (330 g ISCO) and the product was eluted with DCM to afford Intermediate S-1A (13.74 g, 53%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 4.71 (2 H, t, J=6.15 Hz), 2.49-2.86 (2 H, m).
Reaction SMILES: [H-].[Na+].O([C:10]([NH:12][C@H:13]([C:17]([OH:19])=[O:18])[CH:14]([CH3:16])[CH3:15])=[O:11])C1C=CC=CC=1.[CH3:20][NH:21][CH2:22][C:23]1[N:24]=[C:25]([CH:28]([CH3:30])[CH3:29])[S:26][CH:27]=1.Cl.[OH-].[Na+]>C1COCC1.O>[CH3:20][N:21]([C:10]([NH:12][C@H:13]([C:17]([OH:19])=[O:18])[CH:14]([CH3:15])[CH3:16])=[O:11])[CH2:22][C:23]1[N:24]=[C:25]([CH:28]([CH3:30])[CH3:29])[S:26][CH:27]=1
Reactant: CC(C)[C@H](NC(=O)Oc1ccccc1)C(=O)O
Reactant: CNCc1csc(C(C)C)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)O)C(C)C)cs1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred slurry of 95% NaH (355 mg, 14.1 mmol) at -5° C. in 15 mL of THF was added a solution of N-phenoxycarbonyl-L-Valine (2.99 g, 12.6 mmol) and N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amine (2.16 g, 12.7 mmol) in 15 mL of THF followed by a 5 mL THF rinse. The reaction mixture was stirred at or below 0° C. for three hours and then allowed to warm to ambient temperature. After two days at ambient temperature, the THF was removed under reduced pressure. The remaining aqueous residue was added to 31 mL of methyl tert-butyl ether and treated with stirring with a solution of 0.15 mL (1.8 mmol) of concentrated hydrochloric acid in 30 mL of water. The pH of the solution was adjusted to ~9 with 10% sodium hydroxide solution. The aqueous phase was washed with 30 mL of methyl tert-butyl ether. The aqueous phase was treated with 30 mL of toluene and acidified to pH 3 with 4 N HCl. The aqueous layer was separated and extracted with an additional 30 mL aliquot of toluene. The combined toluene extracts were concentrated under reduced pressure. The title compound was crystallized from toluene-heptane as a crystalline solid (3.32 g, 84%). m.p. 82.8-93.8° C. 1H NMR (CDCl3, 400 MHz) δ 1.02 (d, 3H), 1.04 (d, 3H), 1.38 (d, 6H), 2.30 (m, 1H), 2.30 (m, 1H), 3.00 (s, 3H), 3.28 (m, 1H), 4.24 (dd, 1H), 4.48 (AB quartet, 2H), 6.10-6.14 (br s, 1H), 7.02 (s, 1H). 13C NMR (CDCl3, 400 MHz) δ 18.1, 19.5, 23.0, 23.1, 29.9, 33.1, 34.9, 49.2, 59.6, 114.4, 149.4, 151.5, 159.8, 174.9. IR (film) 3200-3400, 1730,1620 cm-1. High Resolution MS Calc for C14H23N3SO3 : (FAB) m/e 314.1538 (M+H)+. Found: 314.1530.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[CH:3]1[CH2:7][N:6]2[C:8](=[O:28])[C:9]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13](S(C)(=O)=O)[N:12]=3)[N:5]2[CH2:4]1.[CH3:30][C@H:31]([NH2:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:29])[CH:3]1[CH2:7][N:6]2[C:8](=[O:28])[C:9]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:38][C@H:31]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH3:30])[N:12]=3)[N:5]2[CH2:4]1
Reactant: C[C@H](N)c1ccccc1
Reactant: CN(C)C1Cn2c(-c3ccnc(S(C)(=O)=O)n3)c(-c3ccc(F)cc3)c(=O)n2C1
Solvent: Cc1ccccc1
Product: C[C@H](Nc1nccc(-c2c(-c3ccc(F)cc3)c(=O)n3n2CC(N(C)C)C3)n1)c1ccccc1
Temperature: 140 °C

Procedure:
A solution of the crude 6-dimethylamino-2-(4-fluorophenyl)-3-(2-methanesulfonyl-pyrimidin-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazol-1-one, 25, prepared as described herein above (4.2 g, 10 mmol) and (S)-(−)-α-methyl-benzyl amine (45.2 mL, 351 mmol) are dissolved in toluene (100 mL). The resulting mixture is heated to 140° C. for 12 hours, cooled to room temperature and the solvent removed in vacuo. The resulting residue is purified over silica (1:1 EtOAc/hexanes) to afford the desired product.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:35])[N:8]([CH2:31][C:32](O)=[O:33])[C:9](=[O:30])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]2[NH:28][C:27](=[O:29])[O:26][N:25]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[C:36]([NH2:40])([CH3:39])([CH3:38])[CH3:37].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(OCC)(=O)C.CN(C)C=O>[C:36]([NH:40][C:32](=[O:33])[CH2:31][N:8]1[C:9](=[O:30])[C:10]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[NH:28][C:27](=[O:29])[O:26][N:25]=3)=[CH:16][CH:17]=2)=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:6]=[C:7]1[CH3:35])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)N
Reactant: CCCCc1nc(C)n(CC(=O)O)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(C)n(CC(=O)NC(C)(C)C)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 66.3 %

Procedure:
A mixture of [4-butyl-2-methyl-6-oxo-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-1(6H)-yl]acetic acid (0.10 g), tert-butylamine (0.02 g), 1-hydroxybenzotriazole (0.03 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.044 g) and N,N-dimethylformamide (3 mL) was stirred at room temperature for 15 hr. The reaction mixture was diluted with ethyl acetate, washed with diluted hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.074 g, 66%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:51])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33]([O:35]CC3C=CC=CC=3)=[O:34])[N:28]([C:43]3[CH:48]=[CH:47][C:46]([F:49])=[C:45]([F:50])[CH:44]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:51])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33]([OH:35])=[O:34])[N:28]([C:43]3[CH:48]=[CH:47][C:46]([F:49])=[C:45]([F:50])[CH:44]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)OCc3ccccc3)n(-c3ccc(F)c(F)c3)n2)CC1
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)O)n(-c3ccc(F)c(F)c3)n2)CC1
Reaction time: 16 h

Procedure:
To a solution of 4.800 g 4-((S)-2-{[5-Benzyloxycarbonylmethoxy-1-(3,4-difluoro-phenyl)-1H-pyrazole-3-carbonyl]-amino}-4-tert-butoxycarbonyl-butyryl)-piperazine-1-carboxylic acid ethyl ester in 60 ml ethyl acetate were added under argon 0.7 g Pd/C (10%) and the suspension was stirred under an atmosphere of hydrogen (3 bar) for 16 h. The suspension was filtered over a plug of Celite® and washed with ethyl acetate. The crude product obtained after evaporation of the solvent was dried under vacuo. Yield: 4.0 g.