Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH:6]([NH:10][C:11](=[O:31])[CH:12]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=1)[C:13]([CH3:17])([CH3:16])[CH2:14][OH:15])([CH2:8][CH3:9])[CH3:7]>N1C=CC=CC=1>[CH:6]([NH:10][C:11]([CH:12]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[C:21]([C:27]([F:29])([F:30])[F:28])[CH:20]=1)[C:13]([CH3:16])([CH3:17])[CH2:14][O:15][S:2]([CH3:1])(=[O:4])=[O:3])=[O:31])([CH2:8][CH3:9])[CH3:7]
Reactant: CS(=O)(=O)Cl
Reactant: CCC(C)NC(=O)C(Oc1ccc(C#N)c(C(F)(F)F)c1)C(C)(C)CO
Solvent: c1ccncc1
Product: CCC(C)NC(=O)C(Oc1ccc(C#N)c(C(F)(F)F)c1)C(C)(C)COS(C)(=O)=O
Temperature: 2.5 °C
Reaction time: 5 h

Procedure:
Methanesulfonyl chloride (36.45 g, 318 mmol) was added in one portion to a cold (0-5° C.) sol'n of the N-sec-butyl-2-(4-cyano-3-trifluoromethyl phenoxy)-4-hydroxy-3,3-dimethylbutyramide (5, 79.0 g, 212 mmol) in 200 mL pyridine. The reaction mixture was stirred at 0-5° C. for 5 h. The reaction was quenched with 800 mL sat'd aq. NH4Cl and extracted with 1000 mL CH2Cl2. The organic phase was washed with 2N aq. HCl (3×300 mL) and then half sat'd aq. NaCl (3×300 mL). The organic was conc'd under vac (35-40° C.) to an amber gum.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].ClC1C=CC(S(C)(=O)=O)=CC=1[C:22](O)=[O:23].N1CCC(CO)C1>>[OH:23][CH2:22][CH:16]1[CH2:17][CH2:18][N:14]([C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])[CH2:15]1
Reactant: CS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Agent: OCC1CCNC1
Product: CS(=O)(=O)c1ccc(N2CCC(CO)C2)c(C(=O)O)c1
Yield: 39 %

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 5-Methanesulfonyl-2-pyrrolidin-1-yl-benzoic acid (Example Y) from 2-Chloro-5-methanesulfonyl-benzoic acid and rac-pyrrolidin-3-yl-methanol and obtained in 39% yield. MS (m/e): 298.1 (M−H, 100%).
Reaction SMILES: [O:1]=[C:2]([N:18]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH2:22][CH2:21][CH2:20][CH2:19]1)[CH2:3][NH:4][C:5]1[C:6]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:8]=[CH:9][CH:10]=1.[C:29](Cl)(=[O:34])[CH2:30][C:31](Cl)=[O:32]>C1COCC1>[O:1]=[C:2]([N:18]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH2:22][CH2:21][CH2:20][CH2:19]1)[CH2:3][N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:31](=[O:32])[CH2:30][C:29]1=[O:34]
Reactant: O=C(Cl)CC(=O)Cl
Reactant: O=C(CNc1ccccc1Nc1ccccc1)N1CCCCc2ccccc21
Solvent: C1CCOC1
Product: O=C(CN1C(=O)CC(=O)N(c2ccccc2)c2ccccc21)N1CCCCc2ccccc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To 100 mL of THF at 0° C. was added dropwise over 20 min simultaneously a solution of 8.0 g of the N1-[2-oxo-2-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)ethyl]-N2-phenylbenzene-1,2-diamine (8.0 g, 21.5 mM) in 100 mL of THF and solution of malonyl dichloride (2.40 mL, 25.8 mM) in 100 mL of THF. The resulting solution was stirred at RT for 20 h and the solvent removed in vacuo. The resultant material was purified by silica gel flash column chromatography using hexanes/EtOAc 1/1 and the combined filtrates evaporated in vacuo to give 7.5 g of product.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([CH2:11][N:12]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[NH:14][C:13]3=[O:21])=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:22]([O:24][C:25](=[O:31])/[CH:26]=[CH:27]/[CH2:28][CH2:29][CH3:30])[CH3:23].[OH-].C([N+](C)(C)C)C1C=CC=CC=1.CO.[NH4+].[Cl-]>CN(C=O)C.O>[CH2:22]([O:24][C:25](=[O:31])[CH2:26][CH:27]([N:14]1[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:12]([CH2:11][C:9]2[C:10]3[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]=3[S:7][CH:8]=2)[C:13]1=[O:21])[CH2:28][CH2:29][CH3:30])[CH3:23]
Reactant: Cc1cccc2scc(Cn3c(=O)[nH]c4ccccc43)c12
Reactant: CCC/C=C/C(=O)OCC
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(CC(=O)OCC)n1c(=O)n(Cc2csc3cccc(C)c23)c2ccccc21
Temperature: 60 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
To a solution of 1-(4-Methyl-benzo[b]thiophen-3-ylmethyl)-1,3-dihydro-benzimidazol-2-one (50 mg, 0.17 mmol) in dry DMF (1.0 mL) are added (E)-Hex-2-enoic acid ethyl ester (27 mg, 0.19 mmol) and 40% benzyltrimethyl ammonium hydroxide in MeOH (0.008 mL, 0.017 mmol). The resulting mixture is warmed up to 60° C. for 16 hr. Then another 27 mg of (E)-Hex-2-enoic acid ethyl ester is added the heating is continued for another 8 hr. Then saturated NH4Cl (2 mL) and water (10 mL) are added and the mixture is extracted with EtOAc (3×25 mL). The organic layers are combined, dried over MgSO4 and concentrated to give the crude product. Purification with flash column chromatography using 20% EtOAc in Hexanes affords 70 mg (95%) of 3-[3-(4-Methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-hexanoic acid ethyl ester.
Reaction SMILES: CO[C:3](=[O:23])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:24][NH:25][C:26]([NH2:28])=[O:27].C[O-].[Mg+2].C[O-].CO>>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:3]([NH:28][C:26]([NH:25][CH3:24])=[O:27])=[O:23])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CNC(N)=O
Reactant: COC(=O)C(CC1CCCC1)c1ccc(-c2cccnc2)cc1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: CNC(=O)NC(=O)C(CC1CCCC1)c1ccc(-c2cccnc2)cc1
Temperature: 25 °C
Yield: 5.4 %

Procedure:
A mixture of 3-cyclopentyl-2-(4-pyridin-3-yl-phenyl)-propionic acid methyl ester (275 mg, 0.89 mmol) and methyl urea (165 mg, 2.22 mmol) was treated with a solution of magnesium methoxide in methanol (7.4 wt. %, 5.5 mL, 2.67 mmol). The reaction mixture was then concentrated in vacuo to approximately one-half the volume of methanol. The resulting reaction mixture was then heated under reflux for 3 d. The reaction mixture was allowed to cool to 25° C. and then partitioned between water and ethyl acetate. The layers were separated, and the aqueous layer was further extracted with ethyl acetate (2×40 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/3 hexanes/ethyl acetate) afforded 1-[3-cyclopentyl-2-(4-pyridin-3-yl-phenyl)-propionyl]-3-methyl-urea (17 mg, 6%) as a white solid: mp 158-160° C.; FAB-HRMS m/e calcd for C21H25N3O2 (M+H)+ 352.2025, found 352.2028.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([NH2:6])=[O:5])[CH3:3].[NH:7]([C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[C@H:8]([C:16]([O:18]CC1C=CC=CC=1)=O)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.NCC(N)=O>>[NH:7]([C:26]([O:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:27])[C@H:8]([C:16]([NH:1][C@H:2]([C:4]([NH2:6])=[O:5])[CH3:3])=[O:18])[CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: C[C@H](N)C(N)=O
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Agent: NCC(N)=O
Product: C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(N)=O
Reaction time: 24 h

Procedure:
In all cases, the reaction of L-Ala-NH2 (6) with Z-L-Phe-OBn (1) was slower than Gly-NH2 (5) with Z-L-Phe-OBn (1). Further, after 24 hours, Z-L-Phe-Ala-NH2 (11) was obtained in moderate yield (33-57%) using WT, S166C—SCH2C6H5, —SCH2C6F5, and —SCH2(p-COOH—C6H4) as the catalysts. However, Z-L-Phe-Ala-NH2 (11) was obtained in 88% yield in the case of S166C—SCH2CH2NH3+. Unlike S166C—SCH2CH2NH3+, the use of M222C—SCH2CH2NH3+ did not improve the yield of the dipeptide product as compared to the WT-catalyzed reaction; only a low 22% yield of Z-L-Phe-Ala-NH2 (11) was obtained. This was possibly due to the steric interaction of this residue at the binding site, S1 pocket, with the P1 substrate as mentioned above.
Reaction SMILES: [Na].[N+:2]([C:5]1[CH:6]=[C:7]([CH:26]=[CH:27][CH:28]=1)[CH:8]=[C:9]([C:23]([CH3:25])=O)[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:11])([O-:4])=[O:3].Cl.[C:30]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])(=[NH:32])[NH2:31]>C(O)C>[NH2:31][C:30]1[NH:32][C:23]([CH3:25])=[C:9]([C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:11])[CH:8]([C:7]2[CH:26]=[CH:27][CH:28]=[C:5]([N+:2]([O-:4])=[O:3])[CH:6]=2)[C:33]=1[C:34]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: CCOC(=O)CC(=N)N
Reactant: CCCCCCCCCCOC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCCCCCCCCCOC(=O)C1=C(C)NC(N)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Reaction time: 0.25 h

Procedure:
A solution of 1.15 g (50 mmol) of sodium in 100 ml of ethanol was added dropwise at room temperature, with stirring, to a solution of 18.8 g (50 mmol) of decyl 2-(3-nitrobenzylidene)acetoacetate and 8.3 g (50 mmol) of ethyl amidinoacetate hydrochloride in 250 ml of ethanol. The mixture was then heated to boiling for 15 minutes. After standing overnight, the precipitated sodium chloride was filtered off, the filtrate was evaporated in vacuo and the oily residue was brought to crystallization by trituration with ether/petroleum ether. The crude product was filtered off with suction and recrystallized from ethanol, melting point: 190°-191° C.
Reaction SMILES: C[O:2][C:3](=[O:28])[C@H:4]([CH2:7][O:8][C:9]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:5][CH3:6].[OH-].[Na+]>CO>[CH3:6][NH:5][C@H:4]([C:3]([OH:28])=[O:2])[CH2:7][O:8][C:9]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2
Reactant: CN[C@@H](COC1(c2ccccc2)c2ccccc2-c2ccccc21)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN[C@@H](COC1(c2ccccc2)c2ccccc2-c2ccccc21)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.4 %

Procedure:
To a solution of 0.032 g (0.085 mmol) N-methyl--O--(9-phenyl-9H-fluoren-9-yl)-L-serine methyl ester from Step 1 in methanol (1 mL) was added 20% sodium hydroxide (1 mL) and the mixture stirred at room temperature for 1 h. Most of the ethanol was evaporated under vacuo, the residue suspended in water (5 mL) nd extracted with diethyl ether (2×1 mL). The alkaline aqueous phase was acidified with 20% acetic acid by cooling with an ice bath, the white precipitate was filtered, washed with water and dried in vacuo over P2O5 to give 0.027 g (yield 90%) N-methyl--O--(9-phenyl-9H-fluoren-9-yl)-L-serine as a white powder.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@@:4]1([C:17]([N:19]2[CH2:28][CH2:27][C:26]3[N:25]=[CH:24][C:23]([C:29]([F:32])([F:31])[F:30])=[CH:22][C:21]=3[CH2:20]2)=[O:18])[CH2:8][C@H:7]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[CH:5]1.[OH2:33]>CC(C)=O>[C:12]([O:11][C:10]([NH:9][C@H:7]1[CH2:8][C@@:4]([CH2:3][C:2]([OH:33])=[O:1])([C:17]([N:19]2[CH2:28][CH2:27][C:26]3[N:25]=[CH:24][C:23]([C:29]([F:32])([F:31])[F:30])=[CH:22][C:21]=3[CH2:20]2)=[O:18])[CH:5]=[CH:6]1)=[O:16])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C=C[C@](CCO)(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Reactant: O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H]1C=C[C@](CC(=O)O)(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Reaction time: 2 h

Procedure:
To a solution of the product of Example 1, Step D (508 mg, 1.12 mmol, 1 eq) in acetone (10 mL) at 0° C. was added Jones oxidation solution (0.46 mL, 1.23 mmol, 1.1 eq). After 2 hr, water was added, the aqueous was extracted with ethyl acetate, the organics combined, dried over MgSO4 and concentrated to afford the product of Step A that was used unpurified in the next step. Calculated for C22H26F3N3O5: 492.2 (M+23). found: 492.1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.I[CH:24]([CH3:26])[CH3:25]>>[CH:24]([O:1][C:2]1[CH:3]=[N:4][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])=[CH:13][CH:14]=2)=[N:6][CH:7]=1)([CH3:26])[CH3:25]
Reactant: CC(C)I
Reactant: CC(=O)NC(C)CCc1ccc(Oc2ncc(O)cn2)cc1
Product: CC(=O)NC(C)CCc1ccc(Oc2ncc(OC(C)C)cn2)cc1

Procedure:
N-{3-[4-(5-Hydroxypyrimidin-2-yloxy)phenyl]-1-methylpropyl}acetamide (125 mg, 0.41 mg) was reacted with 2-iodopropane in analogy to example 36f. Yield: 9 mg (6%), M+H+: 344.14.
Reaction SMILES: [F:1][CH:2]([F:16])[C:3]1[N:8]2[N:9]=[C:10]([C:12]([OH:14])=O)[N:11]=[C:7]2[N:6]=[C:5]([CH3:15])[CH:4]=1.[NH2:17][C:18]1[CH:19]=[C:20]([C:24]([C:26]2[C:34]3[CH:33]=[N:32][CH:31]=[N:30][C:29]=3[N:28]([CH:35]([CH3:37])[CH3:36])[CH:27]=2)=[O:25])[CH:21]=[N:22][CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:35]([N:28]1[C:29]2[N:30]=[CH:31][N:32]=[CH:33][C:34]=2[C:26]([C:24]([C:20]2[CH:19]=[C:18]([NH:17][C:12]([C:10]3[N:11]=[C:7]4[N:6]=[C:5]([CH3:15])[CH:4]=[C:3]([CH:2]([F:1])[F:16])[N:8]4[N:9]=3)=[O:14])[CH:23]=[N:22][CH:21]=2)=[O:25])=[CH:27]1)([CH3:37])[CH3:36]
Reactant: Cc1cc(C(F)F)n2nc(C(=O)O)nc2n1
Reactant: CC(C)n1cc(C(=O)c2cncc(N)c2)c2cncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(F)F)n2nc(C(=O)Nc3cncc(C(=O)c4cn(C(C)C)c5ncncc45)c3)nc2n1
Temperature: 50 °C
Reaction time: 16 h
Yield: 12 %

Procedure:
7-Difluoromethyl-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carboxylic acid (29.64 mg, 0.130 mmol) was added to (5-amino-pyridin-3-yl)-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone (28.1 mg, 0.1 mmol), HATU (49.42 mg, 0.130 mmol) and DIPEA (22.4 uL, 0.13 mmol) in anhydrous DMF (1 mL). The mixture was stirred at 50° C. for 16 hours and then evaporated in vacuo and purified by prep-HPLC (method 5) to afford the title compound in 12% yield, 6.1 mg.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][N:14]3[CH:17]=[CH:18][N:19]=[C:13]3[CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.CC1(C)C(C)(C)[O:24][B:23](B2OC(C)(C)C(C)(C)O2)[O:22]1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[N:19]1[CH:18]=[CH:17][N:14]2[CH:15]=[CH:16][C:11]([NH:10][C:4]3[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=[C:2]([B:23]([OH:24])[OH:22])[N:3]=3)=[CH:12][C:13]=12
Reactant: Cn1cc(Br)nc(Nc2ccn3ccnc3c2)c1=O
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Product: Cn1cc(B(O)O)nc(Nc2ccn3ccnc3c2)c1=O
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
A 100-mL round-bottomed flask equipped with a reflux condenser was charged with 185a (638 mg, 1.99 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (Pin2B2, 2.54 mg, 10 mmol), 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) (163 mg, 0.18 mmol), CS2CO3 (1.3 g, 3.98 mmol), and 1,4-dioxane (20 mL). After bubbling nitrogen through the mixture for 30 minutes, it was heated at 80° C. under nitrogen atmosphere for 3 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was diluted with petroleum ether (150 mL) and ethyl acetate (15 mL). The resulting suspension was stirred at room temperature for 30 minutes. The solid was collected by filtration and further purified by silica-gel column chromatography eluting with dichloromethane/methanol (60/1 to 15/1) to afford 185b (400 mg, 70%) as an off-white solid. MS-ESI: [M+H]+ 286
Reaction SMILES: [CH3:1][CH:2]1[N:6]([CH2:7][CH2:8][CH2:9][CH2:10]Br)[C:5](=[O:12])[CH2:4][S:3]1.Cl.[Cl:14][C:15]1[CH:16]=[C:17]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:18]=[CH:19][CH:20]=1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>CC#N>[ClH:14].[Cl:14][C:15]1[CH:16]=[C:17]([N:21]2[CH2:26][CH2:25][N:24]([CH2:10][CH2:9][CH2:8][CH2:7][N:6]3[C:5](=[O:12])[CH2:4][S:3][CH:2]3[CH3:1])[CH2:23][CH2:22]2)[CH:18]=[CH:19][CH:20]=1
Reactant: CC1SCC(=O)N1CCCCBr
Reactant: Clc1cccc(N2CCNCC2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: CC1SCC(=O)N1CCCCN1CCN(c2cccc(Cl)c2)CC1

Procedure:
To a solution of 2-methyl-3-(4-bromobutyl)-4-thiazolidinone (4.0 g) and 1-(3-chlorophenyl)piperazine hydrochloride (3.69 g) in 100 ml of dry CH3CN were added K2CO3 (8.8 g) and NaI (200 mg). The mixture was heated to reflux with stirring under N2.
Reaction SMILES: [CH:1]1([NH:6][CH2:7][C:8]([OH:15])([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>C(#N)C>[CH2:16]([N:6]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)[CH2:7][C:8]([OH:15])([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C(C)(O)CNC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)C(C)(O)CN(Cc1ccccc1)C1CCCC1
Temperature: 80 °C
Yield: 76.4 %

Procedure:
To ethyl 3-(cyclopentylamino)-2-hydroxy-2-methylpropanoate (3.9 g, 18 mmol) in 50 ml of acetonitrile at room temperature, was added benzyl bromide (3.2 ml, 27.2 mmol) dropwise, followed by K2CO3 (7.5 g, 54.3 mmol). The reaction mixture was heated at 80° C. for 18 h. It was then diluted to EtOAc, washed by brine and water. Organic extract dried and concentrated to a residue, which was purified on silica gel column chromatographically (Hex/EtOAc=100:1 to 10:1) to give 4.2 g product (77%). [M+H] calc'd for C18H27NO3, 306; found 306.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]2[O:10][CH2:9][CH2:8][O:7]2)=[CH:2]1.[CH2:11]([Li])CCC.CI.O>O1CCCC1.CCCCCC>[CH3:11][C:2]1[S:1][CH:5]=[CH:4][C:3]=1[CH:6]1[O:10][CH2:9][CH2:8][O:7]1
Reactant: c1cc(C2OCCO2)cs1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: Cc1sccc1C1OCCO1
Temperature: -10 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
A solution of 2-(thiophen-3-yl)-1,3-dioxolane (33.6 g) synthesized above in tetrahydrofuran (300 mL) was cooled to −10° C., 1.6M n-butyllithium in hexane solution (148 mL) was added dropwise, and the mixture was stirred for 1 hr under a nitrogen atmosphere. The reaction mixture was cooled to −78° C., methyl iodide (16.1 mL) was added, and the mixture was stirred at −78° C. for 30 min, and then at room temperature for 5 hr. Water was added to quench the reaction, the organic solvent was evaporated using evaporator, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% ethyl acetate/hexane) to give the title compound (26.0 g, 71%) as a yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17](=[N:19][NH:20][C:21]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[C:25]([N+:33]([O-:35])=[O:34])[CH:24]=3)=[O:22])[CH3:18])[C:12]=2[OH:36])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CO.[OH-].[Na+].Cl>O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17](=[N:19][NH:20][C:21]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([OH:29])=[O:28])=[C:25]([N+:33]([O-:35])=[O:34])[CH:24]=3)=[O:22])[CH3:18])[C:12]=2[OH:36])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc(C(=O)NN=C(C)c2nn(C)c(-c3ccc(C(C)(C)C)cc3)c2O)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=NNC(=O)c1ccc(C(=O)O)c([N+](=O)[O-])c1)c1nn(C)c(-c2ccc(C(C)(C)C)cc2)c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.5 %

Procedure:
To methyl 4-[(2-{1-[5-(4-tert-butylphenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethylidene}hydrazino)carbonyl]-2-nitrobenzoate (0.945 mmol, 466.2 mg), methanol (33 mL) was added, and 1 M aqueous sodium hydroxide (4.7 mmol, 4.7 mL) was added. After about 26 hours of stirring at room temperature and 3 hours of stirring at 40° C., 1 M hydrochloric acid (4.7 mmol, 4.7 mL) and water were added. The precipitated solid was recovered by filtration, washed with water and dried by means of a vacuum pump. The resulting yellow solid (359.5 mg) was dissolved in THF (50 mL) and stirred at room temperature for 2 days. The insolubles were filtered off, and the filtrate was concentrated and dried by means of a vacuum pump. After addition of chloroform, the precipitated solid was recovered by filtration and dried by means of a vacuum pump to give the desired product as a pale yellow solid (260.7 mg, yield 58%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[O:10][C:11]3[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:4][C:3]=1[C@:22]1([CH3:34])[C:28]([F:30])([F:29])[C:27]([CH3:32])([CH3:31])[O:26][CH2:25][C:24](=O)[NH:23]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:44])=CC=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[O:10][C:11]3[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:4][C:3]=1[C@:22]1([CH3:34])[C:28]([F:30])([F:29])[C:27]([CH3:32])([CH3:31])[O:26][CH2:25][C:24](=[S:44])[NH:23]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1(C)OCC(=O)N[C@](C)(c2cc(-c3nc4ccc(C(F)(F)F)cc4o3)c(F)cc2F)C1(F)F
Product: CC1(C)OCC(=S)N[C@](C)(c2cc(-c3nc4ccc(C(F)(F)F)cc4o3)c(F)cc2F)C1(F)F
Yield: 67 %

Procedure:
In a manner analogous to that described in Example 2b), the reaction of (R)-5-[2,4-difluoro-5-(6-trifluoromethyl-benzo oxazol-2-yl)-phenyl]-6,6-difluoro-5,7,7-trimethyl-[1,4]oxazepan-3-one (163 mg, 332 μmol) with Lawesson's reagent (145 mg, 359 μmol) yielded the title compound (113 mg, 67% yield as a white solid. MS (ISP): m/z=507.1 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:17]([NH2:19])=[O:18])=[N:15][CH:16]=3)=[CH:8][C:7]=2[CH:20]=1.C(Cl)Cl.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:17]([NH2:19])=[O:18])=[N:15][CH:16]=3)=[CH:8][C:7]=2[CH:20]=1
Reactant: COc1ccc2oc(-c3ccc(C(N)=O)nc3)cc2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: NC(=O)c1ccc(-c2cc3cc(O)ccc3o2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.5 %

Procedure:
5-(5-Methoxy-benzofuran-2-yl)-pyridine-2-carboxylic acid amide (0.21 mmol) was mixed with CH2Cl2 (3 mL) at 0° C. under argon atmosphere. BBr3 (1M in CH2Cl2) (1.0 mL) was added dropwise and the mixture was stirred for 2 h at rt. The mixture was hydrolysed with H2O followed by NaHCO3 (sat. aq.). The resulting mixture was filtered, and the obtained precipitate was washed with H2O and EtOAc. The solid was dried at 40° C. for 15 h under vacuum to give the title compound (20 mg). 1H NMR δ ppm 9.08 (d, 1 H) 8.33 (dd, 1 H) 8.20 (br. s., 1 H) 7.97 (d, 1 H) 7.61 (br. s., 1 H) 7.54 (s, 1 H) 7.47 (d, 1 H) 7.02 (d, 1 H) 6.85 (none, 1 H); MS m/z 255 (M+H).