Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].Cl[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:7].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20][CH3:21].C(OCC)(=O)C.CCCCCC>C(Cl)(Cl)Cl>[Cl:13][C:14]1[CH:19]=[C:18]([C:6](=[O:7])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:17]=[CH:16][C:15]=1[S:20][CH3:21]
Reactant: CCOC(=O)C(=O)Cl
Reactant: CSc1ccccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=O)c1ccc(SC)c(Cl)c1
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
To a well stirred solution of AlCl3 (16.58 g, 2 eq) in chloroform (100 mL), ethyl (chlorocarbonyl)formate (10.02 g (8.35 mL), 1.6 eq) was added at 0° C. and the contents were allowed to stir for 30 min. Then (2-chlorophenyl)(methyl)sulfane (10 g (8.33 mL), 0.06 mol) was added at 0° C. and the overall reaction mass was allowed to stir for 3-4 h at room temperature. Progress of the reaction was monitored by TLC (5% ethyl acetate/hexane, Rf˜0.3). On completion of the reaction, crushed ice was added and the contents were allowed to stir for 10 min. The organic layer was separated and the aqueous layer was extracted with DCM (2×100 mL). The combined extract was dried over sodium sulfate and concentrated under reduced pressure to yield ethyl 2-(3-chloro-4-(methylthio)phenyl)-2-oxoacetate as a pale yellow colored liquid (12 g, 73%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[S-:11][C:12]#[N:13].[NH4+].[CH3:15][NH:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][CH:21]=[CH:20]2>CC(C)=O>[ClH:1].[CH3:15][N:16]([C:12]1[S:11][C:2]2[N:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4](=[O:5])[N:13]=1)[C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][CH:21]=[CH:20]2
Reactant: N#C[S-]
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: CNc1ccc2ncccc2c1
Agent: [NH4+]
Solvent: CC(C)=O
Product: CN(c1ccc2ncccc2c1)c1nc(=O)c2cccnc2s1
Product: Cl

Procedure:
The reaction procedure of Example 102 was followed except that 334 mg of 2-chloronicotinoyl chloride, 145 mg of ammonium thiocyanate, 300 m of 6-(methylamino)quinoline and 7 ml of acetone were used. The resulting crude product was then washed with hot ethanol to obtain 324 mg of 2-[N-methyl-N-(quinolin-6-yl)amino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5].[C:17]([N:25]=[C:26]=[S:27])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCOCC>[C:17]([NH:25][C:26]([NH:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5])=[S:27])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Nc1ccccc1C(=O)Nc1ccccc1
Solvent: CCOCC
Product: O=C(NC(=S)Nc1ccccc1C(=O)Nc1ccccc1)c1ccccc1
Yield: 97.8 %

Procedure:
To a stirred mixture of 10 g of 2-amino-N-phenylbenzamide and 500 ml of ether was added dropwise, a solution of 7.7 g of benzoyl isothiocyanate in 100 ml of ether over 20 minutes. After standing several hours the solid was collected, giving 17.3 g of 2-[[(benzoylamino)thioxomethyl]amino]-N-phenylbenzamide.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([Cl:4])=[O:3].[OH:7][CH:8]([CH3:22])[CH2:9][C:10]([O:13][O:14][C:15]([CH3:21])([CH3:20])[CH2:16][CH:17]([OH:19])[CH3:18])([CH3:12])[CH3:11].[Cl-:23]>CC(OC)(C)C>[Cl:23][C:2]([C:1]([O:19][CH:17]([CH3:18])[CH2:16][C:15]([O:14][O:13][C:10]([CH3:12])([CH3:11])[CH2:9][CH:8]([O:7][C:1]([C:2]([Cl:4])=[O:3])=[O:5])[CH3:22])([CH3:20])[CH3:21])=[O:5])=[O:3]
Reactant: CC(O)CC(C)(C)OOC(C)(C)CC(C)O
Reactant: O=C(Cl)C(=O)Cl
Reactant: [Cl-]
Solvent: COC(C)(C)C
Product: CC(CC(C)(C)OOC(C)(C)CC(C)OC(=O)C(=O)Cl)OC(=O)C(=O)Cl
Yield: 82.7 %

Procedure:
A 250 mL three-neck flask equipped with a magnetic stirrer, a thermometer and an addition funnel was charged with 50.8 g (400 mmoles) of oxalyl chloride and 75 mL of MTBE. Then to the resulting solution was slowly added 24.7 g (100 mmoles) of 95% di(3-hydroxy-1,1-dimethylbutyl) peroxide over a period of 30 minutes at 21°-30° C. The addition funnel was then replaced with a nitrogen gas tube and dry nitrogen gas wasslowly bubbled through the reaction mass in order to remove HCl over a period of 4 hours at 25°-30° C. The MTBE, excess oxalyl chloride, and any remaining gas were removed in vacuo using a water aspirator. Obtained was 38.2 g (97% of theory, uncorrected) of a amber liquid. An IR spectrum of the product showed no OH bands and showed a pairof carbonyl bands at 1790 cm-1 and 1755 cm-1. Based on hydrolyzable chloride content the assay of the product was 85.0% and the corrected yield was 82.7%.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:28][C:29](=O)[CH2:30][C:31]1[CH:32]=[N:33][NH:34][CH:35]=1>>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:12][N:13]1[C:29](=[O:28])[CH2:30][C:31]1[CH:32]=[N:33][NH:34][CH:35]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1cn[nH]c1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCC1
Product: COc1ccc(N2CCN(C(=O)Cc3cn[nH]c3)[C@@H](Cc3ccccc3)C2)cc1OC1CCC1
Yield: 14 %

Procedure:
Prepared using the same procedure described in Example 275 from (S)-3-benzyl-1-(3-cyclobutyloxy-4-methoxy-phenyl)-piperazine and (1H-pyrazol-4-yl)-acetic acid methyl ester with heating for 17 days to afford the title compound as an off-white solid (20 mg, 14%). LC/MS (Method B) 3.42 min, [M+1]+ 461.
Reaction SMILES: OO.C(O[C:10]([C:12](F)(F)F)=[O:11])(C(F)(F)F)=O.CN(C)CCNC1N=[N+:23]([O-:35])[C:24]2[CH:33]=[C:32]3[C:28]([CH2:29][CH:30](C)[CH2:31]3)=[CH:27][C:25]=2[N:26]=1.C(O)(C(F)(F)F)=[O:38]>C(Cl)Cl.N>[N+:23]([C:24]1[CH:33]=[C:32]2[C:28]([CH2:29][CH2:30][CH2:31]2)=[CH:27][C:25]=1[NH:26][C:10](=[O:11])[CH3:12])([O-:35])=[O:38]
Reactant: CC1Cc2cc3nc(NCCN(C)C)n[n+]([O-])c3cc2C1
Reactant: O=C(O)C(F)(F)F
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: N
Agent: OO
Solvent: ClCCl
Product: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])CCC2
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
H2O2 (70%, 0.65 mL, ca. 12.9 mmol) was added dropwise to a stirred solution of TFAA (1.8 mL, 12.9 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 96 (371 mg, 1.3 mmol) and TFA (0.50 mL, 6.5 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 20° C. for 6 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCl3 (4×30 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give (i) starting material 96 (181 mg, 49%) and (ii) 1,4-dioxide 97 (103 mg, 26%) as a red solid: mp (MeOH/DCM) 149-151° C.; 1H NMR δ 8.09 (s, 1H, H-9), 8.07 (s, 1H, H-5), 7.52 (br s, 1H, NH), 3.58-3.64 (m, 2H, CH2N), 3.14-3.27 (m, 2H, CH2), 2.63-2.75 (m, 3H, CH, CH2), 2.59 (br t, J=6.0 Hz, 2H, CH2), 2.28 [s, 6H, N(CH3)2], 1.18 (d, J=6.2 Hz, 3H, CH3); 13C NMR δ 155.6, 149.4, 145.5, 138.0, 128.9, 115.8, 111.8, 57.4, 45.0 (2), 41.4, 40.4, 38.7, 34.8, 20.1. Anal. calcd for C15H21N5O2.½CH2Cl2: C, 54.6; H, 6.3; N, 19.9. Found: C, 54.4; H, 6.0; N, 19.8%.
Reaction SMILES: FC1C(O[C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=C(F)C(F)=C(F)C=1F.[CH2:29]([C:31]1[CH2:35][CH:34]([CH2:36][O:37][NH2:38])[O:33][N:32]=1)[CH3:30]>>[CH2:29]([C:31]1[CH2:35][CH:34]([CH2:36][O:37][NH:38][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)[O:33][N:32]=1)[CH3:30]
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1ccccc1NCc1ccncc1
Reactant: CCC1=NOC(CON)C1
Product: CCC1=NOC(CONC(=O)c2ccccc2NCc2ccncc2)C1

Procedure:
Prepared by a similar method as described for example 415. Starting materials: 2-[(Pyridin-4-ylmethyl)-amino]-benzoic acid pentafluorophenyl ester (preparation 7C) and O-(3-ethyl-4,5-dihydro-isoxazol-5-ylmethyl)-hydroxylamine (see preparation 90).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][C@@H:13]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[C:14]2[CH:19]=[CH:18][C:17](/[C:20](=[N:22]/[OH:23])/[NH2:21])=[CH:16][CH:15]=2)[CH2:7]1)=[O:5])[CH3:2].[C:32]1([C:38]2[C:42]([C:43]([F:46])([F:45])[F:44])=[C:41]([C:47](Cl)=O)[O:40][N:39]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CCN(C(C)C)C(C)C>C(#N)C>[Si:25]([O:24][C@@H:13]([C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:21]=[C:47]([C:41]3[O:40][N:39]=[C:38]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:42]=3[C:43]([F:46])([F:44])[F:45])[O:23][N:22]=2)=[CH:18][CH:19]=1)[CH2:12][N:8]1[CH2:9][CH2:10][CH2:11][C@H:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7]1)([C:28]([CH3:30])([CH3:29])[CH3:31])([CH3:27])[CH3:26]
Reactant: O=C(Cl)c1onc(-c2ccccc2)c1C(F)(F)F
Reactant: CCOC(=O)[C@H]1CCCN(C[C@@H](O[Si](C)(C)C(C)(C)C)c2ccc(/C(N)=N/O)cc2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)[C@H]1CCCN(C[C@@H](O[Si](C)(C)C(C)(C)C)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)C1
Temperature: 3 °C
Reaction time: 0.5 h
Yield: 1282 %

Procedure:
(S)-Ethyl-1-((S)-2-(tert-butyldimethylsilyloxy)-2-(4-((Z)-N′-hydroxycarbamimidoyl)phenyl)ethyl)piperidine-3-carboxylate (32.6 g, 72 5 mmol) was dissolved in acetonitrile (145 ml) (anhydrous) and cooled to ˜3° C. with ice-bath. 3-phenyl-4-(trifluoromethyl)isoxazole-5-carbonyl chloride (19.98 g, 72.5 mmol) was dissolved in 50 mL anhydrous acetonitrile and added dropwise. The internal temperature was kept below 10° C. during addition. After addition, the reaction mixture was allowed to warm to room temperature. At 30 minutes, HPLC showed completion of the first reaction step. The reaction mixture was re-cooled to below 10° C. DIEA (18.99 ml, 109 mmol) was added slowly. After the addition, the reaction mixture was heated up to 55° C. for 17 hrs. HPLC/LCMS showed completion of the reaction. The solvents were removed by ROTAVAPOR®. The residue was stirred in 250 mL 20% EtOAc/hexanes and the DIPEA HCl salt precipitated from solution and was removed via filtration. The filtrate was concentrated and purified using a silica gel cartridge (3×330 g silica, 0-50% EtOAc/hexanes gradient). (S)-ethyl 1-((S)-2-(tert-butyldimethylsilyloxy)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-3-carboxylate (43g, 64.1 mmol, 88% yield) was obtained a light yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 8.16 (2H, d), 7.68 (2H, d), 7.57 (5H, m), 4.85 (1H, m), 4.14 (2H, m), 2.95 (1H, m), 2.82 (1H, m), 2.64 (1H, dd), 2.51 (1H, m), 2.49 (1H, dd), 2.35 (1H, tt), 2.14 (1H, dt), 1.91 (1H, m), 1.66 (1H, dt), 1.57 (1H, m), 1.48 (1H, m), 1.27 (3H, t), 0.92 (9H, s), 0.11 (3H, s), −0.05 (3H, s).
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[C:13]([CH3:15])[CH3:14])=[CH:8][N:7]=1)([O:3][CH2:4][CH3:5])=[O:2].[O:16]1CCOCC1>O>[C:1]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[C:13]([CH3:14])[CH:15]=[O:16])=[CH:8][N:7]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: C1COCCO1
Reactant: CCOC(=O)c1ccc(C=C(C)C)cn1
Solvent: O
Product: CCOC(=O)c1ccc(C=C(C)C=O)cn1
Temperature: 100 °C
Yield: 53 %

Procedure:
A mixture of 5.0 g (45.0 mmol) of SeO2 and 4.25 g (20.7 mmol) of 1-(2-carbethoxy-5-pyridyl)-2-methyl-1-propene in 50 mL of dioxane and 2 mL of H2O was degassed three times under argon and then heated at 100° C. for 2 h. The mixture was filtered through Celite and washed with dioxane. The filtrate was concentrated and chromatographed on 150 g of silica gel (50% EtOAc/hexane and 75% EtOAc/hexane) to give 2.95 g of 3-(2-carbethoxy-5-pyridyl)-2-methyl-2-propenal as a yellow solid. Analytical LC (Radialpak B, 25% EtOAc/hexane) indicated about 5% of the Z isomer was present. Recrystallization from EtOAc/hexane gave 2.4 g (53% yield) of the pure E isomer as white crystals, mp 72°-73° C.; IR (mull) 1740, 1700, 1330, 1300, 1260, 1200, 1170, 1140, 1120, 1020, 920, 880, 830, 810, 720 cm-1 ; 1H NMR (CDCl3) δ1.50 (t, J=7 Hz, 3, CO2CH2CH3), 2.10 (s, 3, C=CCH3), 4.50 (q, J=7 Hz, 2, CO2CH2CH3), 7.35 (s, 1, C=CH), 8.02 (dd, J=2 Hz, J=8 Hz, 1, 4'--H), 8.27 (d, J=8 Hz, 1, 3'--H), 8.93 (d, J=1 Hz, 1, 6'--H), 9.70 (s, 1, CHO); MS calcd for C12H13NO3 219.0895, found 219.0907.
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][C:4]1[C:9]([CH2:10]Cl)=[CH:8][CH:7]=[C:6]([Cl:12])[N:5]=1>C(#N)C>[Cl:3][C:4]1[C:9]([CH2:10][NH:2][CH3:1])=[CH:8][CH:7]=[C:6]([Cl:12])[N:5]=1
Reactant: CN
Reactant: ClCc1ccc(Cl)nc1Cl
Solvent: CC#N
Product: CNCc1ccc(Cl)nc1Cl
Yield: 83.7 %

Procedure:
In 50 ml of acetonitrile was dissolved 7.8 g (0.1 mole) of 40% aqueous methylamine and with stirring and ice-cooling, a solution of 3.9 g (0.02 mole) of 2,6-dichloro-3-pyridylmethyl chloride in 10 ml of acetonitrile was added dropwise over 5 minutes. After completion of the dropwise addition, the mixture was stirred at room temperature for 2 hours and, then, concentrated. The residue was extracted with ether (30 ml×3) and dried over MgSO4. Finally, the solvent was distilled off to give 3.2 g of the title compound as a pale yellow oil.
Reaction SMILES: [CH3:1][CH:2]([NH:4][C:5]([C:7](=O)C=CC1C=CC=C(OC)C=1)=[O:6])[CH3:3].Cl[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([O:28]O)=O)[CH:21]=1.S(C1C(C)=CC(O)=C(C(C)(C)C)C=1)C1C(C)=C[C:34]([OH:41])=C(C(C)(C)C)C=1>C(Cl)CCl>[CH3:1][CH:2]([NH:4][C:5]([CH:7]1[CH:26]([C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([O:41][CH3:34])[CH:21]=2)[O:28]1)=[O:6])[CH3:3]
Reactant: COc1cccc(C=CC(=O)C(=O)NC(C)C)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(O)c(C(C)(C)C)cc1Sc1cc(C(C)(C)C)c(O)cc1C
Solvent: ClCCCl
Product: COc1cccc(C2OC2C(=O)NC(C)C)c1

Procedure:
This compound was prepared from N-(1-methylethyl)-3-methoxycinnamoylcarboxamide (43.9 g.), m-chloroperbenzoic acid (46 g.), 4,4'-thiobis(6-tert-butyl-m-cresol) (0.6 g.), and ethylene dichloride (500 ml.) as described in Example 7. The compound obtained as an oil was used directly in the subsequent reaction.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br:15]C1COCCO1>>[Br:15][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:5]=1)=[O:3]
Reactant: COC(=O)Cc1ccc(C(C)=O)cc1
Reactant: BrC1COCCO1
Product: COC(=O)Cc1ccc(C(=O)CBr)cc1

Procedure:
Prepared from methyl 4-acetyl-phenylacetate and bromodioxan.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([N:9]1[CH:12]([S:13][N:14]2[C:18](=[O:19])[C:17]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]3[C:15]2=[O:24])[CH:11]([NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:10]1=[O:36])[C:6]([CH3:8])=[CH2:7])=[O:4].C1OC1C.[Br:41]N1C(=O)CCC1=O>ClCCCl.[Hg]>[CH3:1][O:2][C:3]([CH:5]([N:9]1[CH:12]([S:13][N:14]2[C:15](=[O:24])[C:16]3=[CH:23][CH:22]=[CH:21][CH:20]=[C:17]3[C:18]2=[O:19])[CH:11]([NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:10]1=[O:36])[C:6]([CH2:8][Br:41])=[CH2:7])=[O:4]
Reactant: C=C(C)C(C(=O)OC)N1C(=O)C(NC(=O)COc2ccccc2)C1SN1C(=O)c2ccccc2C1=O
Reactant: O=C1CCC(=O)N1Br
Agent: CC1CO1
Agent: [Hg]
Solvent: ClCCCl
Product: C=C(CBr)C(C(=O)OC)N1C(=O)C(NC(=O)COc2ccccc2)C1SN1C(=O)c2ccccc2C1=O
Yield: 34.3 %

Procedure:
To a solution of 1-(1-methoxycarbonyl-2-methylprop-2-enyl)-3-phenoxyacetamido-4-phthalimidothio-azetidin-2-one 3.6 g (7 mmoles) in 230 ml of 1,2-dichloroethane were added 5 ml of propylene oxide and 1.9 g (10.5 mmoles) of N-bromosuccinimide. The mixture was irradiated under nitrogen for 2 hours at 14° C with a Hanovia TQ 150 mercury high pressure lamp using a Pyrex filter. After washing twice with 150 ml of a 0.067 molar aqueous potassium phosphate solution buffered to pH 5.8, washing twice with 100 ml of water, drying and treating with decolorizing charcoal, the reaction mixture was concentrated. After adding a mixture of ethyl acetate, diethyl ether and n - hexane, the precipitate was chromatographed on silica gel (methylene chloride ethyl acetate 9:1 (v/v) to obtain 1.3 g (2.4 mmoles; 34% yield) of 1-(1-methoxycarbonyl-2-bromomethylprop-2-enyl)-3-phenoxyacetamido-4-phthalimidothio-azetidin-2-one.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]([C:15]2[CH:39]=[CH:38][C:18]3[N:19]([CH2:22][C:23]4[CH:28]=[CH:27][C:26](B5OC(C)(C)C(C)(C)O5)=[CH:25][CH:24]=4)[CH:20]=[N:21][C:17]=3[CH:16]=2)=[O:14])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].Br[C:41]1[C:42]([C:47]([O:49][CH3:50])=[O:48])=[N:43][CH:44]=[CH:45][CH:46]=1.C([O-])([O-])=O.[Na+].[Na+].O>COCCOC.C1COCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]([C:15]2[CH:39]=[CH:38][C:18]3[N:19]([CH2:22][C:23]4[CH:24]=[CH:25][C:26]([C:41]5[C:42]([C:47]([O:49][CH3:50])=[O:48])=[N:43][CH:44]=[CH:45][CH:46]=5)=[CH:27][CH:28]=4)[CH:20]=[N:21][C:17]=3[CH:16]=2)=[O:14])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc([C@H](C)NC(=O)c2ccc3c(c2)ncn3Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c1
Reactant: COC(=O)c1ncccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: C1CCOC1
Product: COC(=O)c1ncccc1-c1ccc(Cn2cnc3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)cc1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
The mixture of (S)—N-(1-(3-isopropylphenyl)ethyl)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-benzo[d]imidazole-5-carboxamide (94 ma, 0.18 mmol), methyl 3-bromopicolinate (20 mg, 0.09 mmol), Pd(PPh3)4 (11 mg, 0.009 mmol) and Na2CO3 (19 mg, 0.18 mmol) in DME/THF/H2O (2.5 mL/1 mL/1 mL) was heated to 100° C. and stirred for 18 hrs under N2. Then the mixture was poured into 10 mL of water, and extracted with EtOAc (10 mL×3), the combined organic layers was washed with water (10 mL) and brine (10 mL) and dried with Na2SO4. After filtration, the filtrate was concentrated under the reduced pressure. The residue was purified with prep-TLC (DCM/Methanol=20/1, silica gel) to give the titled compound.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[CH3:13][C:14]1[CH:15]=[CH:16][C:17]([S:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:24][CH:23]=2)=[C:18]([NH2:20])[CH:19]=1>>[CH3:12][C:6]1[N:7]=[C:8]2[C:3]([C:2]([NH:20][C:18]3[CH:19]=[C:14]([CH3:13])[CH:15]=[CH:16][C:17]=3[S:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:24][CH:23]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:5]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: Cc1ccc(Sc2ccc(Oc3ccccc3)cc2)c(N)c1
Product: Cc1ccc(Sc2ccc(Oc3ccccc3)cc2)c(Nc2ccnc3nc(C)ccc23)c1

Procedure:
The product from Example 1d (50 mg, 0.28 mmol) was reacted with the product from Example 70a (86 mg, 0.28 mmol) for 24 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (64 mg, 50%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.37 (s, 3H), 2.73-2.79 (m, 3H), 6.30 (d, J=6.99 Hz, 1H), 6.78-6.87 (m, 2H), 6.97 (d, J=7.72 Hz, 2H), 7.17-7.24 (m, 1H), 7.24-7.28 (m, 2H), 7.32-7.36 (m, 3H), 7.37-7.46 (m, 2H), 7.79 (d, J=8.82 Hz, 1H), 8.42 (d, J=7.35 Hz, 1H), 8.96 (d, J=8.46 Hz, 1H), 11.00 (s, 1H); MS (ESI+) m/z 450 (M+H)+, (ESI−) m/z 448 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12].[CH:13]1([NH2:17])[CH2:16][CH2:15][CH2:14]1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:17][CH:13]2[CH2:16][CH2:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12]
Reactant: NC1CCC1
Reactant: O=S(=O)(Cl)c1ccc(Br)c(F)c1
Solvent: ClCCl
Product: O=S(=O)(NC1CCC1)c1ccc(Br)c(F)c1
Yield: 88.9 %

Procedure:
According to general procedure C, 4-Bromo-3-fluoro-benzenesulfonyl chloride (0.40 g, 1.46 mmol) and cyclobutylamine (0.31 mL, 3.65 mmol) were stirred together with dry dichloromethane (5 mL) for 16 hours. 4-bromo-N-cyclobutyl-3-fluorobenzenesulfonamide (0.40 g, 89%) was provided after purification. MS (ESI) m/z 308. HPLC purity 98.2% at 210-370 nm, 10.6 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[C:10]([CH3:13])[C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl[CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([NH:31][CH3:32])=[O:30])=[C:27]([F:35])[CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[F:35][C:27]1[CH:26]=[C:25]([CH:34]=[CH:33][C:28]=1[C:29](=[O:30])[NH:31][CH3:32])[CH2:24][C:9]1[C:10]([CH3:13])=[C:11]([CH3:12])[C:2]([OH:1])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: CNC(=O)c1ccc(CCl)cc1F
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)c(C)c1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: CNC(=O)c1ccc(Cc2cc(C(=O)OC)c(O)c(C)c2C)cc1F
Temperature: 80 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
To a mixture of methyl 2-hydroxy-3,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.35 g), 4-(chloromethyl)-2-fluoro-N-methylbenzamide (0.23 g) and sodium carbonate (0.24 g) in 1,2-dimethoxyethane (5.40 mL)-water (1.80 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.07 g), and the mixture was stirred overnight at 80° C. under argon atmosphere. To the reaction mixture were added water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.37 g).
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:12])=[CH:7][C:5]([NH2:6])=[C:4]([F:19])[CH:3]=1.[C:20]1(=O)[O:25][C:23](=[O:24])[C:22]2[CH2:26][CH2:27][CH2:28][CH2:29][C:21]1=2.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:12])=[CH:7][C:5]([N:6]2[C:23](=[O:24])[C:22]3[CH2:26][CH2:27][CH2:28][CH2:29][C:21]=3[C:20]2=[O:25])=[C:4]([F:19])[CH:3]=1
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: CCCCCOC(=O)COc1cc(N)c(F)cc1Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCOC(=O)COc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Temperature: 25 °C
Yield: 78 %

Procedure:
A mixture of the compound (II) (12.0 g), 3,4,5,6-tetrahydrophthalic anhydride (7.56 g), triethylamine (0.4 g) and toluene (50 g) was heated under reflux for 10 hours. The reaction mixture was cooled to room temperature and washed with water. The toluene layer was separated and concentrated under reduced pressure. Analysis of the resulting product revealed that it contains the compound (I) in a purity of about 77% and a large amount of a compound of the following formula as the impurity: ##STR6## Purification of the above product by silica gel column chromatography gave the compound (I) (13.7 g).