Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([NH:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].[OH-].[Na+].[CH3:10][O:11][C:12]1[C:13]([CH3:21])=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](Cl)=[O:16]>C(Cl)Cl.O>[CH3:10][O:11][C:12]1[C:13]([CH3:21])=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([NH:7][NH:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:16]
Reactant: CC(C)(C)NN
Reactant: COc1cccc(C(=O)Cl)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COc1cccc(C(=O)NNC(C)(C)C)c1C
Temperature: 25 °C
Yield: 96 %

Procedure:
To a stirred suspension of tert-butylhydrazine hydrochloride (397 g, 3.27 mol) in methylene chloride (2 L) at 0° C., was added sodium hydroxide (50% aqueous, 260 g) diluted with water (400 mL). Following this, 3-methoxy-2-methylbenzoyl chloride (140 g, 0.78 mol) in methylene chloride (1 L) and sodium hydroxide (50% aqueous, 80 g) diluted with water (400 mL) were added concurrently at -20° C. After the addition was complete, the reaction mixture was allowed to warm to room temperature and after additional 30 minutes, the organic layer was washed with water (4×500 mL), dried over magnesium sulfate and stripped to yield N-(3-methoxy-2-methylbenzoyl)-N'-tert-butylhydrazine (177 g, 96% yield). 1H-NMR (CDCl3)δppm 1.19 (s, 9H, t-Bu), 2.29 (s, 3H, CH3), 3.87 (s, 3H, OCH3), 6.90 (d, 1H, C-4 or 6), 6.95 (d, 1H, C-4 or C6) 7.19 (dd, 1H, C-5).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].Cl.[Br:10][C:11]1[CH:12]=[C:13]2[C:17](=[C:18]([C:20]([NH2:22])=[O:21])[CH:19]=1)[NH:16][CH:15]=[C:14]2[CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.O>CN(C)C=O.C(N(CC)CC)C>[Br:10][C:11]1[CH:12]=[C:13]2[C:17](=[C:18]([C:20]([NH2:22])=[O:21])[CH:19]=1)[NH:16][CH:15]=[C:14]2[CH:23]1[CH2:28][CH2:27][N:26]([S:5]([CH2:4][CH2:3][O:2][CH3:1])(=[O:7])=[O:6])[CH2:25][CH2:24]1
Reactant: COCCS(=O)(=O)Cl
Reactant: NC(=O)c1cc(Br)cc2c(C3CCNCC3)c[nH]c12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reaction time: 3 h
Yield: 82.1 %

Procedure:
Under nitrogen, 2-(methyloxy)ethanesulfonyl chloride (43.8 g) was added dropwise over 30 minutes to a cooled, 10° C., suspension of 5-bromo-3-(4-piperidinyl)-1H-indole-7-carboxamide hydrochloride (Intermediate 1, 66 g) in N,N-dimethylformamide (DMF) (350 mL) and triethylamine (77 mL). The reaction mixture was stirred for 3 hours. The reaction mixture was poured into water (2000 mL) and stirred for 1 hour. The resultant solid was collected by filtration and washed with water. The solid was dried in vacuo at 40° C. to give the title compound (67.1 g) as a cream solid.
Reaction SMILES: [I-].[C:2]1([CH:8]([N+:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16]2OCCO2)[CH3:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BrH:21]>>[Br-:21].[CH3:9][C:8]1[N+:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16]=[C:7]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=12
Reactant: Br
Reactant: CC(c1ccccc1)[n+]1ccccc1C1OCCO1
Agent: [I-]
Product: Cc1c2ccccc2cc2cccc[n+]12
Product: [Br-]
Yield: 76 %

Procedure:
A mixture of 1-(1-phenylethyl)-2-(1,3-dioxolan-2-yl)pyridinium iodide (3.5 g, 9 mmol) and 48% hydrobromic acid (20 mL) was refluxed for 16 hours. The solvent was removed in vacuo to afford 1.9 g (76%) of 6-methylbenzo[b]quinolizinium bromide (Formula VII: R2 =H;R1 =CH3 ; Z- =Br-).
Reaction SMILES: [C:1]([CH2:4][C:5](=O)[CH3:6])(=O)[CH3:2].[CH2:8]([NH:10][C:11]([NH2:13])=[O:12])[CH3:9].C(O)C.S(=O)(=O)(O)O>CCOCC>[CH2:8]([N:10]1[C:1]([CH3:2])=[CH:4][C:5]([CH3:6])=[N:13][C:11]1=[O:12])[CH3:9]
Reactant: CCNC(N)=O
Reactant: CC(=O)CC(C)=O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: CCO
Product: CCn1c(C)cc(C)nc1=O
Reaction time: 240 h

Procedure:
Acetylacetone (9.0 g., 0.09 moles) and ethylurea (7.13 g., 0.081 moles) are dissolved in 30 ml. ethanol. The solution is cooled in an ice-water bath while 30 g. of cold concentrated sulfuric acid is added. The resulting yellow solution is stored at room temperature for 10 days and diluted with a large volume of ether. The ether-ethanol mixture is decanted from the thick syrupy residue which is washed with additional fresh ether. The residue is made basic with 2.5 N sodium hydroxide and extracted throughly with methylene chloride. The organic extracts are dried over sodium sulfate, treated with charcoal, filtered, and evaporated under vacuum affording 1-ethyl-4,6-dimethyl-2(1H)-pyrimidinone as a tan solid (7.6 g., 62%).
Reaction SMILES: [C:1]([C:3]1[CH:38]=[CH:37][C:6]([CH2:7][C@@:8]2([CH3:36])[N:12]3[C:13]([S:16]([N:19]4[CH2:23][CH2:22][CH2:21][C@H:20]4[C:24](O)=[O:25])(=[O:18])=[O:17])=[CH:14][N:15]=[C:11]3[N:10]([C:27]3[CH:32]=[C:31]([Cl:33])[CH:30]=[C:29]([Cl:34])[CH:28]=3)[C:9]2=[O:35])=[CH:5][CH:4]=1)#[N:2].CN(C(O[N:47]1N=N[C:49]2[CH:50]=CC=C[C:48]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.F[C:71](F)(F)[C:72]([OH:74])=[O:73]>CN(C=O)C.CCOC(C)=O>[O:73]=[C:72]1[O:74][C@@H:49]([CH2:48][NH:47][C:24]([C@@H:20]2[CH2:21][CH2:22][CH2:23][N:19]2[S:16]([C:13]2[N:12]3[C@@:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:38][CH:37]=4)([CH3:36])[C:9](=[O:35])[N:10]([C:27]4[CH:32]=[C:31]([Cl:33])[CH:30]=[C:29]([Cl:34])[CH:28]=4)[C:11]3=[N:15][CH:14]=2)(=[O:18])=[O:17])=[O:25])[CH2:50][CH2:71]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(S(=O)(=O)N3CCC[C@H]3C(=O)O)n21
Reactant: O=C(O)C(F)(F)F
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(S(=O)(=O)N3CCC[C@H]3C(=O)NC[C@H]3CCC(=O)O3)n21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-1-[(R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-α]imidazole-3-sulfonyl]-pyrrolidine-2-carboxylic acid (see Example 5) (0.1 g, 0.174 mmol) in anhydrous DMF was added the above mixture of amines (0.030 g), followed by TBTU (0.084 g, 0.261 mmol) followed by DIPEA (0.075 mL, 0.435 mmol). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was then diluted with EtOAc and washed with water (x3), 1N HCl, and saturated NaHCO3. The organic phase was dried over Na2SO4 and concentrated. The resulting residue was dissolved in CH2Cl2 and trifluoroacetic acid (1 eq) was added to the solution. The reaction mixture was stirred at room temperature for 3 h and washed with saturated NaHCO3 and water. The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel preparative thin layer chromatography using CH2Cl2—MeOH (95:5) as an eluent to afford 0.063 g of the title compound as a white foam (M+1,671.1).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]([O:13][CH2:14][CH3:15])=[O:12].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:11](=[O:12])[O:13][CH2:14][CH3:15])=[CH:4][CH:3]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)NCc1ccc(Cl)cc1
Reaction time: 3 h
Yield: 98 %

Procedure:
4-Chlorobenzylamine (1.0556 g) was dissolved in pyridine (5 ml), and to the solution was added dropwise ethyl chloroformate.(0.855 ml) during 5 minutes under ice-cooling. After the mixture was stirred for 3 hours, 1N hydrochloric acid was added and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution, and then saturated brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title compound (1.562 g, 98%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[C-:14]#[N:15].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:14]#[N:15])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1
Reactant: FC(F)(F)c1cc(Br)ccc1CBr
Reactant: [C-]#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: N#CCc1ccc(Br)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.1 %

Procedure:
A mixture of 4-methyl-3-trifluorobromobenzene (33.26 g, 104.261 mmol) from step 1 above, KCN (20.43 g, 313.67 mmol) and tetrabutylammonium bromide (3.37 g, 10.45 mmol) in CH2Cl2/H2O 1:1 (300 mL) was stirred at room temperature for 4 hours. The layers were separated and the organic layer washed with H2O (100 mL) 1N HCl (100 mL), brine, dried over Na2SO4 and then concentrated to a brown oil which was purified by flash column chromatography (0% to 20% EtOAc in hexanes) to give the product as a clear oil (14.9 g, 54%). 1H NMR (400 MHz, CDCl3) δ 3.91 (s, 2H), 7.57 (d, J=8.3 Hz, 1 H), 7.75 (dd, J=8.3, 2 Hz, 1 H), 7.84 (d, J=2 Hz, 1 H).
Reaction SMILES: [CH2:1]([Mg]Br)C.C([C:8]1[N:12]2[CH2:13][C@H:14]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=3[F:33])[CH2:15][CH2:16][C@@H:17]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:11]2=[N:10][CH:9]=1)(=O)C.[O:34]1[CH2:38][CH2:37][CH2:36]C1>>[F:33][C:27]1[C:28]([F:32])=[CH:29][CH:30]=[CH:31][C:26]=1[C@H:14]1[CH2:13][N:12]2[C:8]([C:38]([OH:34])([CH3:1])[CH2:37][CH3:36])=[CH:9][N:10]=[C:11]2[C@H:17]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:16][CH2:15]1
Reactant: CC[Mg]Br
Reactant: C1CCOC1
Reactant: CC(=O)c1cnc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2NC(=O)OC(C)(C)C
Product: CCC(C)(O)c1cnc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2NC(=O)OC(C)(C)C
Reaction time: 0.17 h

Procedure:
Ethylmagnesium bromide (3.0 M in ether; 82.0 μL, 0.247 mmol) was added to a solution of tert-butyl (6S,9R)-3-acetyl-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-ylcarbamate (25 mg, 0.062 mmol) in tetrahydrofuran (1 mL) at 0° C. After 10 min, the reaction mixture was quenched with water and the mixture was extracted with dichloromethane (3×). The organic layer was washed with water, saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→60% dichloromethane/ethyl acetate) gave the title compound (17 mg). MS 436.2 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][C:10]([CH2:15][CH3:16])([C:13]#[N:14])[C:9]2=[O:17])[CH:5]=[CH:4][N:3]=1.[N:18]1([C:24]2[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C(O)(=O)C>C(O)CCC>[CH2:15]([C:10]1([C:13]#[N:14])[CH2:11][CH2:12][N:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:28][C:27]3[CH:26]=[CH:25][C:24]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:30][CH:29]=3)[N:7]=2)[C:9]1=[O:17])[CH3:16]
Reactant: CCC1(C#N)CCN(c2ccnc(Cl)n2)C1=O
Reactant: Nc1ccc(N2CCOCC2)cc1
Solvent: CC(=O)O
Solvent: CCCCO
Product: CCC1(C#N)CCN(c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)C1=O
Temperature: 160 °C
Reaction time: 1 h
Yield: 45.6 %

Procedure:
A mixture of 1-(2-chloropyrimidin-4-yl)-3-ethyl-2-oxopyrrolidine-3-carbonitrile (42 mg) obtained in Step A, 4-(morpholin-4-yl)aniline (39 mg) and acetic acid (11 μL) in 1-butanol (2 mL) was stirred in a microwave reactor at 160° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, to the residue was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), and recrystallized (hexane/ethyl acetate) to give the title compound (30 mg).
Reaction SMILES: [CH:1]([N-]C(C)C)([CH3:3])[CH3:2].[Li+].[CH3:9][CH:10]([CH3:39])[CH2:11][CH:12]1[CH2:17][C@@H:16]([CH2:18][O:19][C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:15][C:13]1=[O:14].C(Br)C=C>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH3:9][CH:10]([CH3:39])[CH2:11][C:12]1([C:1]([CH3:3])=[CH2:2])[CH2:17][CH:16]([CH2:18][O:19][C:20]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[O:15][C:13]1=[O:14]
Reactant: CC(C)[N-]C(C)C
Reactant: CC(C)CC1C[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)OC1=O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C=CCBr
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=C(C)C1(CC(C)C)CC(COC(c2ccccc2)(c2ccccc2)c2ccccc2)OC1=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
Lithium diisopropylamide (8.3 mL, 16.6 mmol, 2.0M, heptane/THF/ethylbenzene) is added to a solution of (γS)-α-(2-methylpropyl)-γ-trityloxymethyl-γ-butyrolactone (5.67 g, 13.7 mmol), THF (50 mL), and HMPA (2.9 mL) at -78° C. After stirring for 30 minutes at -78° C., a solution of allyl bromide (1.46 mL, 16.9 mmol) and THF (8.0 mL) is added. The solution is allowed to stir for 4 hours at -78° C. and is then quenched with aqueous ammonium chloride (50 mL). After warming to room temperature, aqueous workup (EtOAc, MgSO4) and purification by flash chromatography (6:1 hexane:EtOAc) to give 5.12 g of the title compound (82%) as a white powder (mp 84°-85° C.).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[N:5][N:6]([CH2:8]Cl)[CH:7]=1.[F:10][C:11]([F:20])([F:19])[CH2:12][CH2:13][CH:14]([C:17]#[N:18])[C:15]#[N:16].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:2][C:3]1[CH:4]=[N:5][N:6]([CH2:8][C:14]([CH2:13][CH2:12][C:11]([F:10])([F:19])[F:20])([C:15]#[N:16])[C:17]#[N:18])[CH:7]=1
Reactant: ClCn1cc(Cl)cn1
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cn1cc(Cl)cn1
Yield: 81.4 %

Procedure:
1.44 g of 4-chloro-1-(chloromethyl)-1H-pyrazole hydrochloride and 1.56 g of (3,3,3-trifluoropropyl) malononitrile were dissolved in 30 ml of N,N-dimethylformamide. 2.76 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.73 g of [(4-chloro-1H-pyrazole-1-yl)methyl](3,3,3-trifluoropropyl) malononitrile (referred as the compound of the present invention (19), hereinafter) shown by below formula.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[C:4](SCC)[N:3]=1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[NH2:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1
Reactant: CCSc1ncc(C(=O)O)c(N)n1
Reactant: C1COCCN1
Product: Nc1nc(N2CCOCC2)ncc1C(=O)O
Temperature: 80 °C
Yield: 8.4 %

Procedure:
A mixture of 4-amino-5-carboxy-2-ethylmercaptopyrimidine (0.35 g, 1.8 mmol) and morpholine (0.5 mL, 10 mmol) was warmed at 80° C. for 4 d and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 4×7.5 cm, eluted with 97.25/2.5/0.25 acetonitrile/water/acetic acid) to yield the product as a white solid (34 mg, 30%).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[CH:8]2)[CH3:2].C1C(=O)N([Br:20])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:20][CH:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[CH:8]2)[CH3:2]
Reactant: CCc1cccc2cccnc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)c1cccc2cccnc12
Temperature: 100 °C
Yield: 77.5 %

Procedure:
A solution of (12) (3.0 g, 19.1 mmol) in carbon tetrachloride (30 mL) was added NBS (5.10 g, 28.6 mmol), and benzoyl peroxide (0.12 g, 0.48 mmol). The mixture was heated at 100° C. for 3 hours. The reaction was cooled to room temperature. The mixture was filtered through filter paper, and washed with ethyl acetate. The filtrate was adsorbed into silica gel. The mixture was purified by chromatography on silica gel with 5 to 15% ethyl acetate in hexane to give 8-(1-bromoethyl)quinoline (13) (3.5 g, 14.8 mmol, 78% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][O:18][CH2:19][C@H:20]([O:29][CH2:30][C:31]([CH3:33])=[CH2:32])[C@@H:21]([O:24][CH2:25][C:26]([CH3:28])=[CH2:27])[CH2:22][OH:23])[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl.CS(C)=O>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][O:18][CH2:19][C@H:20]([O:29][CH2:30][C:31]([CH3:33])=[CH2:32])[C@@H:21]([O:24][CH2:25][C:26]([CH3:28])=[CH2:27])[CH:22]=[O:23])[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C)CO[C@@H](CO)[C@H](COC[C@H](NC(=O)OCc1ccccc1)C(=O)OC)OCC(=C)C
Solvent: ClCCl
Solvent: CS(C)=O
Product: C=C(C)CO[C@@H](C=O)[C@H](COC[C@H](NC(=O)OCc1ccccc1)C(=O)OC)OCC(=C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.6 %

Procedure:
To a solution of (S)-methyl 2-(((benzyloxy)carbonyl)amino)-3-((2S,3S)-4-hydroxy-2,3-bis((2-methylallyl)oxy)butoxy)propanoate (3.96 g, 8.51 mmol) in CH2Cl2/DMSO (56.7 mL, ratio: 5/1) at 0° C. was added TEA (5.93 ml, 42.5 mmol) followed by sulfur trioxide pyridine complex (4.06 g, 25.5 mmol) and the reaction was slowly warmed to room temperature and stirred for 2 h. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic phases were washed with H2O and brine, dried over MgSO4, filtered, and the filtrate was concentrated. The crude residue was purified by flash chromatography (SiO2, hexanes/EtOAc gradient) to provide the title compound as a colorless oil (3.26 g, 83% yield): IR (neat) 3360, 2951, 1721, 1512, 1209, 1053 cm−1; 1H NMR (400 MHz, CDCl3) δ 9.69 (d, J=1.0 Hz, 1H), 7.41-7.27 (m, 5H), 5.65 (d, J=8.7 Hz, 1H), 5.17-5.08 (m, 2H), 4.96-4.92 (m, 2H), 4.90 (d, J=14.8 Hz, 2H), 4.47 (dt, J=8.7, 2.9 Hz, 1H), 4.10 (d, J=12.4 Hz, 1H), 3.97-3.88 (m, 4H), 3.85-3.78 (m, 2H), 3.75 (s, 3H), 3.65 (dd, J=9.5, 3.2 Hz, 1H), 3.62 (d, J=4.5 Hz, 2H), 1.74 (s, 3H), 1.69 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 202.61, 170.65, 156.16, 141.73, 141.27, 136.42, 128.63, 128.26, 128.17, 113.83, 113.23, 82.49, 78.16, 75.45, 75.01, 71.55, 69.39, 67.16, 54.49, 52.70, 19.62, 19.55; ESIMS m/z 486.2 ([M+Na]+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].[F:33][C:34]([F:46])([F:45])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[S:41](Cl)(=[O:43])=[O:42].C(N(C(C)C)CC)(C)C>C(Cl)Cl.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([S:41]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=3[C:34]([F:33])([F:45])[F:46])(=[O:43])=[O:42])[CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCNC2)c1
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(S(=O)(=O)c3ccccc3C(F)(F)F)C2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.1 %

Procedure:
To a solution of compound 33b, 4-Methyl-2-(5-piperidin-3-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (30.5 mg, 0.07mmol) in anhydrous CH2Cl2 (4 ml) was added 2-(Trifluoromethyl)benzene sulfonyl chloride (25.0 mg, 0.10 mmol) and diisopropylethylamine (24 μl, 0.14 mmol). The reaction stirred at room temperature 3 hours, was diluted with EtOAc and washed with sat. NaHCO3, and brine, dried and filtered. Purification by silica gel chromatography (Isco) gave the desired product, (35.4 mg, 79% ). Calcd for C33H35F6NO4S (M+H) 655.69, Found 656.2.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)[O:5][N:4]=1.[SH:17]C(O)C.C(N(CC)CC)C.C[O:29][CH2:30][CH:31](O)C>>[OH:29][CH2:30][CH2:31][S:17][CH2:2][C:3]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)[O:5][N:4]=1
Reactant: O=[N+]([O-])c1cccc(-c2nc(CCl)no2)c1
Reactant: COCC(C)O
Reactant: CC(O)S
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cccc(-c2nc(CSCCO)no2)c1
Temperature: 100 °C

Procedure:
A mixture of 132 g (0.55 mmol) of 3-chloromethyl-5-(3′-nitrophenyl)-1,2,4-oxadiazole (obtainable by reaction of 3-nitrobenzoyl chloride with chloroacetamide oxime), 39.0 ml (0.56 mol) of mercaptoethanol and 80 ml of triethylamine in 700 ml of 1-methoxy-2-propanol was heated to 100° C. for 4 h and, after cooling down, poured onto ice-water. The precipitated solid was filtered off with suction, washed with water and dried at 40° C. under reduced pressure. 142 g of the compound of the formula
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:16][NH2:17])=[N:4][C:5]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])=[N:6][C:7]=1[CH3:8].[CH3:18][C:19](N(C)C)=O.[CH3:24][CH2:25]OC(C)=O>>[Br:1][C:2]1[C:3]([NH:16][N:17]2[CH2:18][CH2:19][CH2:25][CH2:24]2)=[N:4][C:5]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])=[N:6][C:7]=1[CH3:8]
Reactant: CC(=O)N(C)C
Reactant: CCOC(C)=O
Reactant: Cc1nc(-n2c(C)ccc2C)nc(NN)c1Br
Product: Cc1nc(-n2c(C)ccc2C)nc(NN2CCCC2)c1Br
Temperature: 60 °C

Procedure:
To a flask was added 1-(5-bromo-2-(2,5-dimethyl-1H-pyrrol-1-yl)-6-methylpyrimidin-4-yl)hydrazine (100 mg, 0.34 mmol) 1,4-dibromobutane (0.04 ml, 0.37 mmol) hunig's base (0.18 ml, 1.01 mmol) and DMAC (1.0 ml) at R.T. After heating at 60° C. over night, the reaction mixture was cooled to R.T. and diluted with EtOAc (2 ml) the white solid was filtered and the mother liquor was concentrated under reduced pressure. The resulting residue was purified by column chromatography eluted with 30% EtOAc:hex to give the titled compound weighted 76 mg 64%
Reaction SMILES: CCN(CC)CC.[C:8]([C:10]1[N:20]=[CH:19][CH:18]=[CH:17][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:9].[SH2:21]>N1C=CC=CC=1>[C:8]([C:10]1[N:20]=[CH:19][CH:18]=[CH:17][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[S:21])[NH2:9]
Reactant: S
Reactant: CCOC(=O)c1cccnc1C#N
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cccnc1C(N)=S
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Et3N (10 ml) was added to a solution of ethyl 2-cyanonicotinate (1.9 g, 10.78 mmol) in 20 ml of pyridine. Hydrogen sulfide was passed through the reaction mixture at 5° C. for 20 minutes, then the mixture was stirred for 1 hour at room temperature. For work up the solution was purged with nitrogen for 30 minutes, evaporated to dryness, and the remaining solid dissolved in 200 ml of dichloromethane. The organic layer was washed successively with water and brine, dried, evaporated and treated with ethylacetate to give 2.15 g of a red oil which was reacted without further purification.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[CH:19][C:18]([C:21]([NH:23][CH:24]2[CH2:29][CH2:28][CH2:27][N:26]([CH2:30][C:31]([OH:33])=O)[CH2:25]2)=[O:22])=[CH:17][CH:16]=1.[NH2:34][CH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([NH:23][CH:24]2[CH2:29][CH2:28][CH2:27][N:26]([CH2:30][C:31](=[O:33])[NH:34][CH:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH2:25]2)=[O:22])=[CH:19][N:20]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2CCCN(CC(=O)O)C2)cn1
Reactant: NC1CCOCC1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2CCCN(CC(=O)NC3CCOCC3)C2)cn1
Yield: 74 %

Procedure:
As described for example 42, (3-{[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-3-carbonyl]-amino}-piperidin-1-yl-acetic acid (70 mg, 0.16 mmol) was converted, using 4-aminotetrahydropyran instead of methylamine, to the title compound (61 mg, 74%) which was obtained as an off white solid. MS: m/e=534.2 [M+H]+.