Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]([NH:14][S@@:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])[CH3:13])=[C:8]([F:21])[CH:7]=1)=[CH2:5])[CH3:2].Cl[CH2:23]I.C([Zn]CC)C.[NH4+].[Cl-]>C1(C)C=CC=CC=1.CO.C(Cl)Cl>[CH2:1]([O:3][C:4]1([C:6]2[CH:11]=[CH:10][C:9]([C@@H:12]([NH:14][S@@:15]([C:17]([CH3:19])([CH3:18])[CH3:20])=[O:16])[CH3:13])=[C:8]([F:21])[CH:7]=2)[CH2:23][CH2:5]1)[CH3:2]
Reactant: ClCI
Reactant: C=C(OCC)c1ccc([C@H](C)N[S@](=O)C(C)(C)C)c(F)c1
Agent: CC[Zn]CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOC1(c2ccc([C@H](C)N[S@](=O)C(C)(C)C)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.2 %

Procedure:
To a round bottom flask containing (R)—N—((S)-1-(4-(1-ethoxyvinyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (0.49 g, 1.56 mmol) and chloroiodomethane (1.14 mL, 15.6 mmol) in toluene (15 mL) at 0° C. under argon was added diethylzinc (1.0M in hexanes) (15.6 mL, 15.6 mmol). Reaction mixture allowed to warm to room temperature and stirred for 1 hour. Reaction mixture was cooled to 0° C. in an ice bath and to the cold reaction mixture was slowly added a saturated solution of NH4Cl. The aqueous mixture was extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated onto silica gel. Silica gel column chromatography (MeOH/CH2Cl2 0 to 10%) provided (R)—N—((S)-1-(4-(1-ethoxycyclopropyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (145 mg, 0.44 mmol, 28% yield) as a viscous brown oil. 1H NMR (300 MHz, CDCl3) δ 0.93-0.99 (m, 2H) 1.14-1.20 (m, 3H) 1.21 (s, 9H) 1.22-1.27 (m, 2H) 1.57-1.61 (m, 4H) 3.35 (d, J=4.98 Hz, 1H) 3.45 (q, J=7.07 Hz, 2H) 4.77-4.87 (m, 1H) 6.98 (dd, J=7.58, 1.43 Hz, 3H) 7.00-7.03 (m, 4H) 7.28-7.32 (m, 1H). LCMS m/z 328.1 (M+H)+, Rt 0.95 min.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([O:8][CH2:9][CH3:10])=[O:7].[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Cl)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C=O)C>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][N:1]2[CH:5]=[CH:4][N:3]=[C:2]2[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:14][CH:13]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1nccn1Cc1ccc(Cl)cc1

Procedure:
Ethyl 1H-imidazole-2-carboxylate (4 g, 28.5 mmol), p-chlorobenzylchloride (4.38 mL, 34.3 mmol), and sodium carbonate (3.63 g, 34.3 mmol), was dissolved in DMF (8 mL). The solution was stirred at rt for 24 h, at which time water was added and material was extracted with EtOAc. The organic phase was collected, dried over magnesium sulfate, and decanted. Purification accomplished via silica gel flash chromatography (150 g silica, 10% EtOAc/Hexanes to 80% EtOAc/Hexanes.) The title compound was obtained as a clear, yellow-tinted oil. (Yield: 7.28 g, 27.5 mmol, 96%) 1H NMR (400 MHz, CDCl3) 7.25, 7.15, 7.10-7.00, 5.55, 4.34, 1.36
Reaction SMILES: [F:1][C:2]1[C:3](=[N:17][NH2:18])[N:4]=[C:5]([S:15][CH3:16])[NH:6][C:7]=1[NH:8][CH2:9][C:10]1[S:11][CH:12]=[CH:13][N:14]=1.[CH:19]1([CH2:24][C@H:25]([CH2:29][N:30]([CH:38]=[O:39])[O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[C:26](O)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]1.CN1CCOCC1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[CH:19]1([CH2:24][C@@H:25]([C:26]([NH:18][NH:17][C:3]2[C:2]([F:1])=[C:7]([NH:8][CH2:9][C:10]3[S:11][CH:12]=[CH:13][N:14]=3)[N:6]=[C:5]([S:15][CH3:16])[N:4]=2)=[O:27])[CH2:29][N:30]([O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[CH:38]=[O:39])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OC1CCCCO1
Reactant: CSc1nc(=NN)c(F)c(NCc2nccs2)[nH]1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CSc1nc(NCc2nccs2)c(F)c(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OC2CCCCO2)n1
Reaction time: 8 h
Yield: 56.5 %

Procedure:
5-Fluoro-2-(methylthio)-6-[(1,3-thiazol-2-ylmethyl)amino]-4(1H)-pyrimidinone hydrazone (0.1958 g, 0.685 mmol) and (2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoic acid (0.355 g, 0.823 mmol) were dissolved in DMF (5 mL). NMM (0.30 mL, 2.7286 mmol) was added, followed by HOAt (0.112 g, 0.824 mmol) and EDC (0.157 g, 0.819 mmol). After stirring overnight, the reaction mixture was purified by RP-HPLC to provide [(2R)-2-(cyclopentylmethyl)-3-(2-{5-fluoro-2-(methylthio)-6-[(1,3-thiazol-2-ylmethyl)amino]-4-pyrimidinyl}hydrazino)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide as an orange solid (0.2197 g, 57%). LCMS: (M+H)+=568.2.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1.[NH2:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23]>>[ClH:1].[OH:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23])=[CH:3][C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:5]2)=[CH:10][CH:9]=1
Reactant: NCC(O)CO
Reactant: Oc1ccc2c(Cl)cc(-c3ccccc3)nc2c1
Product: Cl
Product: OCC(O)CNc1cc(-c2ccccc2)nc2cc(O)ccc12

Procedure:
The title compound, m.p. 267-268° C., and MS: m/e=310 (M+), was prepared from 4-chloro-2-phenyl-quinolin-7-ol and (RS)-3-amino-1,2-propandiol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][CH2:9][N:8]=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[C:6]=2[CH:19]=1.Cl[CH2:21][CH2:22][C:23]([N:25]=[C:26]=[S:27])=[O:24]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:26]3[S:27][CH2:21][CH2:22][C:23](=[O:24])[N:25]=3)[CH2:10][CH2:9][N:8]=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[C:6]=2[CH:19]=1
Reactant: Clc1ccc2c(c1)C(c1ccccc1Cl)=NCCN2
Reactant: O=C(CCCl)N=C=S
Solvent: C1CCOC1
Product: O=C1CCSC(N2CCN=C(c3ccccc3Cl)c3cc(Cl)ccc32)=N1
Temperature: 25 °C

Procedure:
5 Parts of 7-chloro-5-(o-chlorophenyl)-2,3-dihydro-1H-1,4-benzodiazepine and 12 parts of 3-chloropropionylisothiocyanate is dissolved in 100 parts by volume of tetrahydrofuran and the resultant solution refluxed for about 18 hours. The reaction mixture is then cooled to ambient temperature and filtered. The solvent is removed from the filtrate and the residue crystallized from a mixture of methylene chloride and hexane to afford 7-chloro-5-(o-chlorophenyl)-2,3-dihydro-1-(5,6-dihydro-4-oxo-4H-1,3-thiazin-2-yl)-1H-1,4-benzodiazepine. This compound is represented by the following formula ##STR31##
Reaction SMILES: CN1[CH2:7][CH2:6][C:5]([C:8]2[C:9]([CH3:15])=[N:10][N:11]([CH3:14])[C:12]=2[NH2:13])=[CH:4][CH2:3]1.C(N=[C:19]=[O:20])C.N1C=CC(C)=C(C)[CH:22]=1>>[CH3:22][O:20][C:19]1[N:13]=[C:12]2[N:11]([CH3:14])[N:10]=[C:9]([CH3:15])[C:8]2=[C:5]2[CH2:6][CH2:7][CH2:3][C:4]=12
Reactant: Cc1ccncc1C
Reactant: Cc1nn(C)c(N)c1C1=CCN(C)CC1
Reactant: CCN=C=O
Product: COc1nc2c(c(C)nn2C)c2c1CCC2
Temperature: 25 °C

Procedure:
A mixture of 4-(1,2,5,6-tetrahydro-1-methyl-4-pyridinyl)-1,3-dimethyl-5-(1H)-pyrazolamine (2.06 g; 0.01 mol), 3,4-lutidine (20 ml), ethyl isocyanate (3.16 ml; 0.04 mol), under anhydrous conditions, are heated to the reflux temperature for about 3 hours. The mixture is then cooled to room temperature, concentrated under reduced pressure, washed with ethyl acetate and then with ethyl ether, thus obtaining the product of the title. M.p. 294°-297° C.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C@H:13](OS(C)(=O)=O)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Br-:22].[Na+].O>CN(C)C=O>[Br:22][CH:13]([C:5]1[CH:4]=[C:3]([C:2]([F:21])([F:20])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=1)[CH3:14]
Reactant: [Br-]
Reactant: C[C@@H](OS(C)(=O)=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(Br)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
With reference to Japanese Patent No. 3938651, a solution of (R)-1-[3,5-bis(trifluoromethyl)phenyl]ethanol (optical purity, >99.5% ee; 1.6 g; 6.20 mmol) in dichloromethane (20 mL) was added with methanesulfonyl chloride (0.58 mL, 7.44 mmol), triethylamine (1.30 mL, 9.3 mmol), and dimethylaminopyridine (76 mg, 0.62 mmol) with stirring under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was added with 1 N hydrochloric acid and chloroform at the same temperature, and the organic layer was separated. The aqueous layer was extracted with chloroform (20 mL×3), and the organic layers were combined, washed with saturated brine, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain (R)-methanesulfonic acid 1-[3,5-bis(trifluoromethyl)phenyl]ethyl ester (2.23 g) as colorless oil. Then, a solution of the resulting (R)-methanesulfonic acid 1-[3,5-bis(trifluoromethyl)phenyl]ethyl ester (2.23 g) in N,N-dimethylformamide (20 mL) was added with sodium bromide (1.26 g, 12.25 mmol), and the mixture was stirred at 50° C. for 1 hour. The reaction mixture was added with water (30 mL) at room temperature, and the mixture was extracted with hexane (30 mL×3). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain 1.85 g of 1-bromo-1-[3,5-bis(trifluoromethyl)phenyl]ethane as colorless oil. On the basis of the specific rotation, it was confirmed that the resulting 1-bromo-1-[3,5-bis(trifluoromethyl)phenyl]ethane was obtained after racemization.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[O:7][C:8]1[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=1)[CH2:11][NH:12][C@@H:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1.[CH:26]1[C:31]2[C:32]([O:34][C:35](=[O:36])[C:30]=2[CH:29]=[C:28]2[C:37]([O:39][C:40](=[O:41])[C:27]=12)=[O:38])=[O:33].C(N(C(C)C)CC)(C)C.C([O-])([O-])=[O:52].[Na+].[Na+]>>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[O:7][C:8]1[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=1)[CH2:11][N:12]([C@@H:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1)[C:32]([C:31]1[CH:26]=[C:27]([C:40]([OH:39])=[O:41])[C:28]([C:37]([OH:52])=[O:38])=[CH:29][C:30]=1[C:35]([OH:34])=[O:36])=[O:33]
Reactant: O=c1oc(=O)c2cc3c(=O)oc(=O)c3cc12
Reactant: c1cnc(Oc2cccc(CN[C@H]3CCCc4ccccc43)c2)nc1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)c1cc(C(=O)O)c(C(=O)N(Cc2cccc(Oc3ncccn3)c2)[C@H]2CCCc3ccccc32)cc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product from Example 107A, 1,2,4,5-benzenetetracarboxylic dianhydride (0.125 g, 0.57 mmol) and diisopropylethyl amine (0.4 mL, 2.3 mmol) were processed as described in Example 1B. The reaction mixture was treated with saturated Na2CO3 solution (30 mL) and stirred vigorously at room temperature for 1 hour. The layers were separated and the aqueous layer was acidified with 1N HCl. The acidified aqueous layer was evaporated under reduced pressure to afford a solid. Soxhlet extraction (ethanol) of the crude solid, followed by RP-HPLC, provided the title compound (4 mg).
Reaction SMILES: CS[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[C:12](O)(=O)C.OO.[S:18]([O-:21])([O-])=[O:19].[Na+].[Na+]>O>[CH3:12][S:18]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)(=[O:21])=[O:19]
Reactant: CSc1ccc(C(=O)O)cc1
Reactant: CC(=O)O
Reactant: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Product: CS(=O)(=O)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Yield: 88.1 %

Procedure:
A mixture of 5 g of 4-(methylthio)benzoic acid (97%) and 30 mL of glacial acetic acid was formed. The mixture was cooled in a water bath containing a small amount of ice. To the mixture was added 8.5 g of 30% hydrogen peroxide gradually over one hour. No temperature rise was observed during the addition of the hydrogen peroxide. The reaction mixture was then heated for one and a half hours with the temperature ranging between 70° C. and 100° C. Heating was stopped and the reaction mixture was allowed to cool to room temperature. A solid was present in the reaction mixture. A solution of 3 g of sodium sulfite in 57 g of water was added to the reaction mixture. The solid was filtered from solution and was washed three times with cold deionized water. The solid was transferred to a watchglass and dried overnight. The dried product weighed 5.25 g which is a yield of 88.1% of the theoretical based upon the amount of the starting benzoic acid.
Reaction SMILES: [C:1]([NH:5][C:6](=[S:19])[NH:7][C:8]1[CH:14]=[C:13]([S:15][CH2:16][CH2:17][CH3:18])[CH:12]=[CH:11][C:9]=1[NH2:10])([O:3][CH3:4])=[O:2].CO[C:22]1[CH:23]=[CH:24][C:25]([CH:28]=O)=[CH:26][CH:27]=1.[CH3:30][OH:31]>>[NH:10]=[C:9]1[CH:11]=[CH:12][C:13]([O:31][CH3:30])([S:15][CH2:16][CH2:17][CH3:18])[C:14]([CH2:28][C:25]2[CH:26]=[CH:27][CH:22]=[CH:23][CH:24]=2)=[C:8]1[NH:7][C:6]([NH:5][C:1]([O:3][CH3:4])=[O:2])=[S:19]
Reactant: CCCSc1ccc(N)c(NC(=S)NC(=O)OC)c1
Reactant: CO
Reactant: COc1ccc(C=O)cc1
Product: CCCSC1(OC)C=CC(=N)C(NC(=S)NC(=O)OC)=C1Cc1ccccc1
Temperature: 10 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
To a suspension of 2-(3-carbomethoxy thioureido)-4-propylthioaniline (9.0 g; 0.03 mole) in methanol (100 ml) cooled to 10° C., there is added p=anisaldehyde (4.08 g; 0.03 mole). The mixture is stirred at 10° C. for 1 hr. and at room temperature for 18 hrs. The suspension that forms is vacuum filtered and the filter cake air dried to afford 1-imino-(4-methoxy)phenylmethyl-2-(3-carbomethoxythioureido)-4-propylthiobenzene (9.9 g,; 79%), m.p. 141°-144° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:15]1[S:16][CH:17]=[CH:18][N:19]=1>>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)=[CH:5][CH:4]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Brc1nccs1
Product: FC(F)(F)c1ccc(-c2nccs2)cc1

Procedure:
Using (4-(trifluoromethyl)phenyl)boronic acid (0.5 g, 3.06 mmol) and 2-bromo thiazole (1.1 g, 61.3 mmol) and following the procedure described in Example 7, Step 1, the title compound was obtained after purification by flash chromatography (60-120 mesh, 2% ethyl acetate in hexane) as white solid (0.5 g, 83% Yield). 1H NMR (400 MHz, DMSO-d6): δ 8.15 (d, 2H), 8.00 (d, 1H), 7.90 (d, 1H), 7.85 (d, 2H); LC-MS m/z calculated for [M+H]+ 230.02. found 230.1.
Reaction SMILES: [CH2:1]([C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[CH:7]=[CH:8][C:9](O)=[S:10])[CH2:2][CH2:3][CH3:4].CN(C=O)C.C(Cl)(=O)C([Cl:24])=O>C(Cl)Cl>[CH2:1]([C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[CH:7]=[CH:8][C:9]([Cl:24])=[S:10])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCc1ccccc1C=CC(O)=S
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCc1ccccc1C=CC(=S)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methylene chloride (564 ml) is added to 2-n-butylthiocinnamic acid (40.0 g, 0.69 mol) and cooled in an ice bath. To the mixture is added DMF (13.1 ml, 0.169 mol) and then oxalyl chloride (34.0 ml, 0.389 mol) dropwise with the vigorous evolution of gas. After the oxalyl chloride addition is complete, the ice bath is removed and the reaction stirred at room temperature for 2 hours to afford 2-n-butylthiocinnamic acid chloride. Methylhydroxylamine hydrochloride salt (56.5 g, 0.677 mol) is dissolved in THF (50 ml) and water (70 ml) and further THF (96 ml) is added. The acid chloride is added dropwise then stopped so an additional THF (175 ml) and water (35 ml) can be added for solubility. The acid chloride addition is then continued with the reaction mixture being cooled in an ice bath. After the addition is complete, the reaction mixture is stirred at room temperature overnight.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:30])[CH:10]2[NH:14][C:15](=[O:29])[CH:16]([C:24]([O:26]CC)=[O:25])[N:17]2[CH:21]=[CH:20][CH:19]=[C:18]2[CH:22]=[O:23])[C:7]=1[C:31]([O:33]C(C)(C)C)=[O:32])(=[O:3])[CH3:2]>FC(F)(F)C(O)=O>[C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:30])[CH:10]2[NH:14][C:15](=[O:29])[CH:16]([C:24]([OH:26])=[O:25])[N:17]2[CH:21]=[CH:20][CH:19]=[C:18]2[CH:22]=[O:23])[C:7]=1[C:31]([OH:33])=[O:32])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(C(=O)NC1C(=O)N2C(C(=O)OC(C)(C)C)=C(COC(C)=O)CSC12)n1cccc1C=O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(C(=O)O)n3cccc3C=O)C2SC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
3-[(Acetyloxy)methyl]-7-[[2-carboethoxy-2-(2-formyl-1-pyrryl)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, tert-butyl ester, 0.05 m, is added to 50 ml of trifluoroacetic acid which is maintained at 0° C. The reaction mixture is stirred at 0° C for 15 minutes and then at 10° C for 15 minutes. The trifluoroacetic acid is removed in vacuo, the temperature of the mixture not rising above 20° C. The residue was taken up in methanol-water (4:1) and the pH adjusted to about 4 with ammonium hydroxide. The precipitate is filtered and the filtrate is concentrated and cooled to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][C:7]([CH3:13])=[C:6]([C:14]([OH:16])=[O:15])[C:5]2=[O:17].CN(C)C=O.[C:23](OC(=O)C)(=[O:25])[CH3:24].[C:30](OCC)(=[O:32])[CH3:31]>N1C=CC=CC=1>[C:23]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:30](=[O:32])[CH3:31])[O:8][C:7]([CH3:13])=[C:6]([C:14]([OH:16])=[O:15])[C:5]2=[O:17])(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(C)=O
Reactant: Cc1oc2cc(O)c(O)cc2c(=O)c1C(=O)O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(=O)Oc1cc2oc(C)c(C(=O)O)c(=O)c2cc1OC(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 6,7-dihydroxy-2-methylchromone-3-carboxylic acid (2.24 g), dimethylformamide (30 ml), ethyl acetate (10 ml), pyridine (2.3 ml) and acetic anhydride (2.3 ml) was stirred at room temperature for 3 hours. Ethyl acetate (100 ml) was added to the reaction mixture, and the organic layer was washed successively with 6N-HCl and water, and thereafter dried over anhydrous magnesium sulfate. The solvent was evaporated and ethyl ether was added to the residue. The resulting solid was collected by filtration. It was washed with a 1:1 mixed solvent of ethyl acetate and ethyl ether and then dried, to obtain the desired product (1.93 g).
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([C@H:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[NH2:12])=[CH:3][CH:2]=1.C1CCN2C(=NCCC2)CC1.[CH:25]([S:28](Cl)(=[O:30])=[O:29])([CH3:27])[CH3:26]>C(Cl)Cl>[C:1]1([CH3:13])[CH:2]=[CH:3][C:4]([C@H:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[NH:12][S:28]([CH:25]([CH3:27])[CH3:26])(=[O:30])=[O:29])=[CH:5][CH:6]=1
Reactant: Cc1ccc([C@H]2CCC[C@H]2N)cc1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc([C@H]2CCC[C@H]2NS(=O)(=O)C(C)C)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 100 mL round bottom flask equipped with a magnetic stirrer is charged with (+,−) cis-2-p-tolyl-cyclopentylamine (313 mg, 1.79 mmol, from preparation 9), methylene chloride (5.0 mL) and the solution cooled to 0° C. DBU (0.32 mL, 2.14 mmol) and isopropylsulfonyl chloride (0.24 mL, 2.14 mmol) were added. The reaction was then stirred at 0° C. for 60.0 minutes and brought to room temperature with stirring overnight. The reaction was diluted with methylene chloride and washed with aqueous ammonium chloride, brine and the organic layer dried over sodium sulfate. The title compound was purified by radial chromatography eluting with methylene chloride to give 250 mg (50%) of the purified title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:11]=[C:12]([NH2:20])[C:13]4[CH:14]=[N:15][N:16]([CH3:19])[C:17]=4[CH:18]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.CCN(C(C)C)C(C)C.Cl.[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37](Cl)=[O:38].CO>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:18]=[C:17]4[C:13]([CH:14]=[N:15][N:16]4[CH3:19])=[C:12]([NH:20][C:37]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][N:31]=4)=[O:38])[CH:11]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: Cn1ncc2c(N)cc(-c3cccc4[nH]ccc34)cc21
Reactant: O=C(Cl)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Cn1ncc2c(NC(=O)c3ccccn3)cc(-c3cccc4[nH]ccc34)cc21
Reaction time: 5 h
Yield: 23.2 %

Procedure:
6-(1H-Indol-4-yl)-1-methyl-1H-indazol-4-amine (70 mg, 0.27 mmol) was dissolved in DCM (3 ml) and treated with DIPEA (0.145 ml). 2-Pyridinecarbonyl chloride hydrochloride (59.5 mg, 0.34 mmol) was added and the reaction was stirred for 5 h. MeOH (2 ml) was added and the reaction stirred overnight. The solvent was evaporated and the residue was treated with DCM/Methanol (1:1, 2 ml) then evaporated to dryness. The product was dissolved in DMSO (2 ml) and purified by Mass Directed Automated Preparative HPLC (Method B). Fractions containing product were combined and dried to give the title compound (23 mg).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44][CH3:45])=[C:40]([C:46]([F:49])([F:48])[F:47])[CH:39]=2)[C:35](O)=[O:36])[CH2:32][CH2:31][CH2:30][CH2:29]1.C(N(CC)C(C)C)(C)C.[NH2:59][C:60]1[S:61][CH:62]=[CH:63][N:64]=1.Cl>CN(C)C=O.O>[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44][CH3:45])=[C:40]([C:46]([F:49])([F:48])[F:47])[CH:39]=2)[C:35]([NH:59][C:60]2[S:61][CH:62]=[CH:63][N:64]=2)=[O:36])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: CSc1ccc(C(CC2CCCC2)C(=O)O)cc1C(F)(F)F
Reactant: Nc1nccs1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 43.5 %

Procedure:
A solution of benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (188 mg, 0.42 mmol) and 3-cyclopentyl-2-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-propionic acid (94 mg, 0.28 mmol) in N,N-dimethylformamide (5 mL) was treated with N,N-diisopropylethylamine (150 μL, 0.85 mmol) and 2-aminothiazole (42.5 mg, 0.42 mmol). The mixture was stirred at 25° C. for 48 h. At this time, the reaction mixture was poured into cold water (25 mL) containing a 1N aqueous hydrochloric acid solution (50 mL) and extracted into ethyl acetate (2×75 mL) and diethyl ether (1×25 mL). The combined organic layers were then washed with water (2×75 mL) and a saturated aqueous sodium chloride solution (3×75 mL), dried over magnesium sulfate and sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-N-thiazol-2-yl-propionamide (50.5 mg, 43.1%) as a clear oil: FAB-HRMS m/e calcd for C19H21F3N2OS2 (M+H)+ 415.1125, found 415.1123.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])[CH:6]=[CH:5]2.[CH:22]([C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)=[CH2:23].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][NH:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2](/[CH:23]=[CH:22]/[C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[CH:3]=2)[N:8]=1
Reactant: C=Cc1ccncc1
Reactant: COc1ccccc1CNc1ccc2cc(Br)ccc2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1CNc1ccc2cc(/C=C/c3ccncc3)ccc2n1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
(6-Bromo-quinolin-2-yl)-(2-methoxy-benzyl)-amine (200 mg, 0.583 mmol) was dissolved in 2 mL dimethylformamide. 4-Vinylpyridine (80 mg, 0.762 mmol), triethylamine (77 mg, 0.760 mmol), tri-o-tolylphosphin (7 mg, 0.023 mmol) and palladium(II)acetate (3 mg, 0.013 mmol) were added. The reaction mixture was stirred in a sealed tube at 100° C. for 16 h. The reaction mixture was poured into 30 mL water and extracted three times with ethyl acetate (30 mL each). The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The residue purified by flash chromatography on silica gel (dichloromethane/methanol 100:0->90:10 gradient). The title compound was obtained as a light yellow solid (65 mg, 30%), MS: m/e=368.1 (M+H+).