Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:21][C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=3)=[CH:27][CH:26]=2)=[O:23])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][CH2:17][CH2:18][CH2:19][OH:20])[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][N:39]([CH3:44])[S:40](Cl)(=[O:42])=[O:41].CCN(C(C)C)C(C)C>C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]([NH:21][C:22]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([O:31][C:32]3[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=3)=[CH:29][CH:30]=2)=[O:23])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N:16]([S:40]([N:39]([CH3:44])[CH3:38])(=[O:42])=[O:41])[CH2:17][CH2:18][CH2:19][OH:20])[CH:11]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccncc3)cc2)n(-c2cccc(NCCCO)c2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)N(CCCO)c1cccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccncc3)cc2)c1
Temperature: 40 °C
Reaction time: 8 h
Yield: 44.7 %

Procedure:
A solution of 1-{5-tert-butyl-2-[3-(3-hydroxy-propylamino)-phenyl]-2H-pyrazol-3-yl}-3-[4-(pyridin-4-yloxy)-phenyl]-urea (100 mg, 0.21 mmol) in THF (1 mL) was treated with dimethylsulfamoyl chloride (90 mg, 0.62 mmol, 3 eq) followed by DIEA (30 mg, 0.21 mmol, 1 eq). The reaction mixture was stirred at 40° C. overnight. The mixture was evaporated at reduced pressure, and the product was isolated by MPLC (eluting with 1% to 4% MeOH in DCM) to afford 57 mg (46%) of desired product. 1H-NMR (DMSO-d6) δ 9.08 (s, 1H), 8.40-8.38 (m, 3H), 7.54-7.36 (m, 6H), 7.05 (d, J=8.9 Hz, 2H), 6.84 (d, J=5.6 Hz, 2H), 6.32 (s, 1H), 4.45 (t, J=4.6 Hz, 1H), 3.64 (t, J=7.0 Hz, 2H), 3.33-3.28 (m, 2H), 2.70 (s, 6H), 1.49-1.45 (m, 2H), 1.29 (s, 9H); MS LC-MS [M+H]+=608.2, RT=2.45 min.
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1.ClC1C(Cl)=CC2=NC(=O)N=C2C=1.C(O[C@@H:29]1[O:41][C@H:40]([CH2:42][O:43][C:44](=[O:46])[CH3:45])[C@@H:35]([O:36][C:37](=[O:39])[CH3:38])[C@H:30]1[O:31][C:32](=[O:34])[CH3:33])(=O)C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>CCOC(C)=O>[Br:1][C:2]1[N:3]([C@@H:29]2[O:41][C@H:40]([CH2:42][O:43][C:44](=[O:46])[CH3:45])[C@@H:35]([O:36][C:37](=[O:39])[CH3:38])[C@H:30]2[O:31][C:32](=[O:34])[CH3:33])[C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1
Reactant: Clc1cc2nc(Br)[nH]c2cc1Cl
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C1N=c2cc(Cl)c(Cl)cc2=N1
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of (7) (47.867 g, 180 mmol) in 540 mL of dry. MeCN, was added 45 mL (180 mmol) of BSA. The reaction mixture was stirred at room temperature for 15 min to give a clear solution. A small amount of solid impurity remained unsilylated, believed to be 5,6-dichlorobenzimidazol-2-one from the starting material(7). 1,2,3,5-Tetra-O-acetyl-β-D-ribofuranose (60.14 g, 189 mmole) was added to this solution and then TMSOTf (38.267 mL 198 mmol) was added dropwise over 20 min. After the addition had been completed, stirring was continued at room temperature for 30 min. The reaction mixture was diluted with 2 L of EtOAc. The EtOAc solution was washed with 1:1 saturated aquenous NaHCO3 /saturated aquenous NaCl (1.5 L×2), dried (Na2SO4, 100 g), decolorized (activated charcoal, 6 g), and filtered through Celite. The filtrate was evaporated and the residue was recrystallized from MeOH to give 82.21 g (4 crops, 87%) of 52a as white needles. MP: 140°-144° C. This product was pure by 1H NMR.
Reaction SMILES: C([NH:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[C:11](=[O:23])[CH:10]=1)C1C=CC=CC=1>C(O)(=O)C>[NH2:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[C:11](=[O:23])[CH:10]=1
Reactant: O=c1cc(NCc2ccccc2)ccn1Cc1cccc(F)c1
Solvent: CC(=O)O
Product: Nc1ccn(Cc2cccc(F)c2)c(=O)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In a Fischer-Porter bottle, added a solution of 4-(benzylamino)-1-(3-fluorobenzyl)pyridin-2(1H)-one (2.5 g, 8.11 mmol) in glacial acetic acid (20 mL). After the solution was flushed with nitrogen, catalyst was added (10% Pd/C, 2.0 g). The vessel was sealed, evacuated, and purged with hydrogen gas. The system was charged with hydrogen gas (50 psi) and the mixture stirred at room temperature for 4 hours. The system was evacuated and flushed with nitrogen. The reaction mixture was filtered through a bed of celite and washed with fresh ethanol. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography (hexane/ethyl acetate 3:4 v/v). The filtrate was concentrated. 1H-NMR (CD3OD, 400 MHz) δ 7.32 (q, 1H), 7.02 (m, 3H), 5.93 (dd, 1H, J=2.4 Hz, 2.8 Hz), 5.58 (d, 1H, J=2.4 Hz); ES-HRMS m/z 219.0966 (M+H calculated for C12H12N2OF requires 219.0928).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:24][C:25]2[CH:30]=[CH:29][N:28]=[C:27](Cl)[CH:26]=2)=[CH:4][C:5]([F:23])=[C:6]([NH:8][C:9]([N:11]2[CH2:15][CH2:14][N:13]([CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[C:12]2=[O:22])=[O:10])[CH:7]=1.[C:32]([NH2:35])(=[O:34])[CH3:33].C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:32]([NH:35][C:27]1[CH:26]=[C:25]([O:24][C:3]2[C:2]([Cl:1])=[CH:7][C:6]([NH:8][C:9]([N:11]3[CH2:15][CH2:14][N:13]([CH:16]4[CH2:17][CH2:18][O:19][CH2:20][CH2:21]4)[C:12]3=[O:22])=[O:10])=[C:5]([F:23])[CH:4]=2)[CH:30]=[CH:29][N:28]=1)(=[O:34])[CH3:33]
Reactant: CC(N)=O
Reactant: O=C(Nc1cc(Cl)c(Oc2ccnc(Cl)c2)cc1F)N1CCN(C2CCOCC2)C1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(=O)Nc1cc(Oc2cc(F)c(NC(=O)N3CCN(C4CCOCC4)C3=O)cc2Cl)ccn1
Temperature: 100 °C
Yield: 29 %

Procedure:
A mixture of Example C8 (0.243 g, 0.518 mmol), acetamide (0.184 g, 3.11 mmol), Cs2CO3 (0.422 g, 1.294 mmol) and Xantphos (0.090 g, 0.155 mmol) in dioxane (3 mL) was sparged with Ar, treated with Pd2(dba)3 (0.062 g, 0.067 mmol), sparged again with Ar and heated at 100° C. overnight. The mixture was cooled to RT, treated with brine, extracted with EtOAc (3×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified twice via silica gel chromatography (MeOH/DCM, then MeOH/EtOAc) to afford N-(4-((2-acetamidopyridin-4-yl)oxy)-5-chloro-2-fluorophenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide (74 mg, 29%). 1H NMR (400 MHz, DMSO-d6): δ 10.92 (d, J=2.7 Hz, 1 H), 10.57 (s, 1 H), 8.39 (d, J=8.1 Hz, 1 H), 8.17 (d, J=5.7 Hz, 1 H), 7.61 (d, J=2.4 Hz, 1 H), 7.58 (d, J=11.2 Hz, 1 H), 6.64 (dd, J=5.7, 2.4 Hz, 1 H), 3.93-3.83 (m, 3 H), 3.81 (m, 2 H), 3.48 (t, J=8.2 Hz, 2 H), 3.37 (dd, J=12.4, 10.6 Hz, 2 H), 2.03 (s, 3 H), 1.71 (qd, J=12.2, 4.5 Hz, 2 H), 1.62-1.56 (m, 2H); MS (ESI) m/z: 492.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[C:3]([N:16]2[CH2:20][CH2:19][CH:18]([F:21])[CH2:17]2)=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH:5]=[N:6][CH2:7][CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10].[SH:22][C@@H:23]([CH2:27][C:28]([OH:30])=[O:29])[C:24](O)=[O:25]>C1(C)C=CC=CC=1>[CH3:10][C:9]([CH3:12])([CH3:11])[CH2:8][CH2:7][N:6]1[C:24](=[O:25])[C@@H:23]([CH2:27][C:28]([OH:30])=[O:29])[S:22][CH:5]1[C:4]1[CH:13]=[CH:14][CH:15]=[C:2]([F:1])[C:3]=1[N:16]1[CH2:20][CH2:19][C@H:18]([F:21])[CH2:17]1
Reactant: O=C(O)C[C@H](S)C(=O)O
Reactant: CC(C)(C)CCN=Cc1cccc(F)c1N1CCC(F)C1
Solvent: Cc1ccccc1
Product: CC(C)(C)CCN1C(=O)[C@@H](CC(=O)O)SC1c1cccc(F)c1N1CC[C@H](F)C1

Procedure:
N-(3-Fluoro-2-(3-fluoropyrrolidin-1-yl)benzylidene)-3,3-dimethylbutan-1-amine (400 mg, 1.359 mmol) was taken in toluene and (S)-2-mercaptosuccinic acid (204.1 mg, 1.359 mmol) was added. The reaction mixture was refluxed overnight with a Dean Stark trap to remove the water. Then the reaction mixture was concentrated, triturated with ether and dried overnight to give crude 2-((5R)-3-(3,3-dimethylbutyl)-2-(3-fluoro-2-((S)-3-fluoropyrrolidin-1-yl)phenyl)-4-oxothiazolidin-5-yl)acetic acid which was used directly in the next step. The product was identified by HPLC and LC/MS. (LC/MS: m/z=427.2 M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[O:6][C:5](=[O:7])[N:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=2)[C@H:3]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.S(Cl)([Cl:26])=O>C(Cl)Cl>[CH3:1][C:2]1([CH3:23])[O:6][C:5](=[O:7])[N:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([Cl:26])=[O:13])=[CH:10][CH:9]=2)[C@H:3]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=S(Cl)Cl
Reactant: CC1(C)OC(=O)N(c2ccc(C(=O)O)cc2)[C@H]1c1ccccc1
Solvent: ClCCl
Product: CC1(C)OC(=O)N(c2ccc(C(=O)Cl)cc2)[C@H]1c1ccccc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To a vial charged with (S)-4-(5,5-dimethyl-2-oxo-4-phenyloxazolidin-3-yl)benzoic acid (0.200 g, 0.642 mmol) was added DCM (2.57 mL) followed by thionyl chloride (0.469 mL, 6.42 mmol). The vial containing the resulting mixture was sealed and shaken at 40° C. for 2 hours. LC-MS indicated near complete conversion to desired product (primarily methyl ester peak identified). The mixture was dried under reduced pressure providing the product as a light yellow solid. Mass of product not obtained. m/z (ESI) 326.2 (M+H)+ (methyl ester ionization observed).
Reaction SMILES: C([O:5][C:6](=[O:28])[CH2:7][CH2:8][N:9]([C:16]1[S:17][C:18]2[CH2:27][C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:19]=2[N:20]=1)[CH2:10][C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)(C)(C)C.[ClH:29]>O1CCOCC1>[ClH:29].[S:17]1[C:18]2[CH2:27][C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:19]=2[N:20]=[C:16]1[N:9]([CH2:10][C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)[CH2:8][CH2:7][C:6]([OH:28])=[O:5]
Reactant: CC(C)(C)OC(=O)CCN(Cc1cccs1)c1nc2c(s1)Cc1ccccc1-2
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)CCN(Cc1cccs1)c1nc2c(s1)Cc1ccccc1-2

Procedure:
3-[(8H-Indeno[1,2-d]thiazol-2-yl)-thiophen-2-ylmethyl-amino]-propionic acid hydrochloride was prepared (32 mg) following general procedure G1 using 3-[(8H-indeno[1,2-d]thiazol-2-yl)-thiophen-2-ylmethyl-amino]-propionic acid tert-butyl ester (35 mg, 0.085 mmol) and 4 N HCl solution in dioxane (1.0 mL). LCMS m/z: 358 (M+1)+. 1H NMR (CD3OD, 400 MHz): δ 2.8 (t, 3H), 3.80 (s, 2H) 3.9 (t, 2H), 5.0 (s, 2H), 7.08 (dd, 1H), 7.21 (dd, 1H), 7.28 (t, 1H), 7.38 (t, 1H), 7.42 (dd, 1H), 7.56 (dd, 1H), 7.7 (dd, 1H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.Cl.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[S:20][C:19](=[O:21])[N:18]([CH2:22][C:23]([N:25]3[CH2:30][CH2:29][N:28]([NH2:31])[CH2:27][CH2:26]3)=[O:24])[C:17]=2[CH:32]=1.[OH-].[Na+].O>O1CCOCC1>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[S:20][C:19](=[O:21])[N:18]([CH2:22][C:23]([N:25]3[CH2:26][CH2:27][N:28]([NH:31][C:6](=[O:7])[C:5]4[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[CH2:29][CH2:30]3)=[O:24])[C:17]=2[CH:32]=1
Reactant: NN1CCN(C(=O)Cn2c(=O)sc3ccc(Cl)cc32)CC1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(NN1CCN(C(=O)Cn2c(=O)sc3ccc(Cl)cc32)CC1)c1ccc(F)cc1
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
A solution of 4-fluorobenzoyl chloride (761 mg) in dioxane (3 ml) was added dropwise to a mixture of 5-chloro-3-[(4-amino-1-piperazinyl)carbonylmethyl]-2-benzothiazolinone hydrochloride (872 mg), 1N-NaOH (5.3 ml), dioxane (30 ml) and water (5 ml) at 5° C. The resulting mixture was stirred for 30 minutes and concentrated under reduced pressure. The residue obtained was filtered, washed with water and ethyl acetate, and recrystallized from methanol to give 5-chloro-3-{[4-(4-fluorobenzamido)-1-piperazinyl]carbonylmethyl}-2-benzothiazolinone (0.61 g).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][C:11](=[CH:14][C:15]#[CH:16])[CH2:10][CH2:9]2)[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=1.C[Si](C)(C)C#CC=C1CCNCC1.[CH2:33]([O:35][C:36]1[CH:37]=[C:38](Br)[CH:39]=[CH:40][CH:41]=1)[CH3:34].O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[CH2:33]([O:35][C:36]1[CH:41]=[C:40]([C:16]#[C:15][CH:14]=[C:11]2[CH2:12][CH2:13][N:8]([C:6]3[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=3)[CH2:9][CH2:10]2)[CH:39]=[CH:38][CH:37]=1)[CH3:34]
Reactant: C#CC=C1CCN(c2nc(C)ccc2[N+](=O)[O-])CC1
Reactant: CCOc1cccc(Br)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)C#CC=C1CCNCC1
Agent: [F-]
Solvent: O
Product: CCOc1cccc(C#CC=C2CCN(c3nc(C)ccc3[N+](=O)[O-])CC2)c1
Yield: 46 %

Procedure:
The title Compound was prepared from Compound 274c following the procedure described for the compound of Example 274 but using 3-ethoxybromobenzene instead of 1-bromo-3,5-difluorobenzene and adding 1 molar equivalent of tetrabutylammonium fluoride monohydrate to the starting reaction mixture. After the work-up, the residue was purified by automated flash liquid chromatography (SP1™-Biotage) eluting with PE-EtOAc gradient from PE:EtAc 1:0 to 8:2 affording the title product. Yellow solid. Yield: 46%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH:10]=[CH:11][C:12]([N+:14]([O-])=O)=[CH:13][C:8]=3[S:7](=[O:18])(=[O:17])[C:6]=2[CH:19]=1.O1CCOCC1>[Pd].C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH:10]=[CH:11][C:12]([NH2:14])=[CH:13][C:8]=3[S:7](=[O:17])(=[O:18])[C:6]=2[CH:19]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)S(=O)(=O)c1cc(F)ccc1-2
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: Nc1ccc2c(c1)S(=O)(=O)c1cc(F)ccc1-2
Reaction time: 0.5 h
Yield: 76 %

Procedure:
A mixture of 4.2 g of 3-fluoro-7-nitrodibenzothiophene S,S-dioxide, 100 ml of dioxane, 25 ml of glacial acetic acid and 1.0 g of 5% palladium on carbon was hydrogenated for 30 minutes, then filtered through diatomaceous earth and evaporated. The residue was crystallized from 50 ml of acetonitrile, giving 2.85 g of the desired product as yellow crystals, mp 266°-270° C.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[C:12]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([NH:26][C:27]([NH:29][C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=4)=[O:28])=[N:24][CH:25]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[F:36][C:32]1[CH:31]=[C:30]([NH:29][C:27]([NH:26][C:23]2[CH:22]=[CH:21][C:20]([CH2:19][C:12]3[C:13]4[C:14](=[N:15][CH:16]=[CH:17][CH:18]=4)[NH:10][CH:11]=3)=[CH:25][N:24]=2)=[O:28])[CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Nc1cccc(F)c1)Nc1ccc(Cc2cn(S(=O)(=O)c3ccccc3)c3ncccc23)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1cccc(F)c1)Nc1ccc(Cc2c[nH]c3ncccc23)cn1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 1-[5-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-3-(3-fluoro-phenyl)-urea (605, 0.100 g, 0.20 mmol) in tetrahydrofuran (10.0 mL) was added tetrabutylammonium fluoride, trihydrate (0.240 g, 0.76 mmol). The reaction was stirred at room temperature for 5 hours, then poured into water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give a white solid (P-0412, 17.9 mg, 24.8%). MS (ESI) [M+H+]+=362.2.
Reaction SMILES: [C:1](O)(=[O:3])[CH3:2].P(=O)(O)(O)O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH2:23]([C:25]1[C:29]([C:30]2[NH:31][C:32]3[C:37]([CH:38]=2)=[CH:36][CH:35]=[CH:34][CH:33]=3)=[C:28]([CH3:39])[O:27][N:26]=1)[CH3:24]>C(#N)C.CCOCC>[C:1]([C:38]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:31][C:30]=1[C:29]1[C:25]([CH2:23][CH3:24])=[N:26][O:27][C:28]=1[CH3:39])(=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CCc1noc(C)c1-c1cc2ccccc2[nH]1
Agent: O=P(O)(O)O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Solvent: CCOCC
Product: CCc1noc(C)c1-c1[nH]c2ccccc2c1C(C)=O
Reaction time: 0.25 h

Procedure:
To a mixture of 0.77 milliliters (13.45 m mole) of acetic acid and 0.17 grams (1.47 m mole) of 85% phosphoric acid in 10 milliliters of acetonitrile is added, at room temperature, 1.9 milliliters (13.45 m mole) of trifluoroacetic acid anhydride. The mixture is stirred for 15 minutes and then treated by dropwise addition with 1.0 grams (4.42 m mole) of 2-(3-ethyl-5-methyl-4-isoxazolyl)-indole in 10 milliliters acetonitrile. The mixture is stirred for 31/2 hours at room temperature and then poured onto water and extracted with ether. The ether extracts are dried over magnesium sulfate, filtered and evaporated in vacuo. The resulting oil is filtered through silica gel using 10% methanol/methylene chloride. The solvent is evaporated, and the oil obtained is dissolved in ether. The solution is washed with 10% sodium bicarbonate solution, decolorized with charcoal, dried over magnesium sulfate and evaporated in vacuo. The resulting oil crystallizes upon treatment with ether to give 3-acetyl-2-(3-ethyl-5-methyl-4-isoxazolyl)-indole, m.p. 170°-171°.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[N:6]=[CH:7][N:8]2[CH:12]=[C:11]([C:13]3[C@H:14]([CH3:37])[C@@H:15]4[C@@H:32]([C@H:33]([OH:35])[CH3:34])[C:31](=[O:36])[N:16]4[C:17]=3[C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)=[O:19])[S:10][C:9]=12)=[O:4].[I-].[Na+].[NH:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1>CC(C)=O.[Cl-].[Na+].O>[OH:35][C@@H:33]([C@H:32]1[C:31](=[O:36])[N:16]2[C:17]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)=[O:19])=[C:13]([C:11]3[S:10][C:9]4=[C:5]([C:3](=[O:4])[CH2:2][N:40]5[CH2:44][CH2:43][CH2:42][CH2:41]5)[N:6]=[CH:7][N:8]4[CH:12]=3)[C@H:14]([CH3:37])[C@H:15]12)[CH3:34]
Reactant: C1CCNC1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)CCl)c4s3)[C@H](C)[C@H]12
Agent: [Cl-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)CN5CCCC5)c4s3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
4-Nitrobenzyl (1S,5R,6S)-2-(7-chloroacetylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (161 mg) was dissolved in 5 ml of acetone to prepare a solution. Sodium iodide (67 mg) was added to the solution, and the mixture was stirred at room temperature for 1.5 hr. Brine was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate. The solvent was removed by distillation, and the residue was dissolved in 5 ml of N,N-dimethylformamide to prepare a solution. Pyrrolidine (0.03 ml) was added to the solution, and the mixture was stirred at room temperature for 2 hr. Brine was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate. The solvent was removed by distillation, and the residue was washed with diethyl ether to give 4-nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(pyrrolidin-1-yl)acetylimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][OH:35])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl.O>[C:11]([O:30][CH2:31][CH2:32][CH2:33][CH:34]=[O:35])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=CCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -70 °C
Reaction time: 0.17 h
Yield: 79.8 %

Procedure:
To a solution of 43.9 g of oxalyl chloride in 0.52 l of dichloromethane, pre-cooled to -70° C., was added over 35 min a solution of 62.9 g of dimethylsulfoxide in 0.10 l of dichloromethane. The solution was stirred for 10 min at -70° C. Then, a solution of 76.5 g of 4-trityloxy-1-butanol in 0.3 l of dichloromethane was added over 35 min, the temperature being maintained at -65° to -70° C. Stirring was continued for another 20 min, and then, 92.9 g of triethylamine were added over 10 min at -60° to -70° C. The mixture was stirred for 20 min at -70° C., and then allowed to warm to 20° C. over 45 min. After the addition of 0.5 l of water, stirring was continued for 15 min. The layers were separated and the aqueous phase was extracted with 0.6 l of dichloromethane. The organic phase was washed with 0.6 l of water and dried over sodium sulfate, and the solvent was evaporated in vacuo. The residue was crystallized from hexane to yield 60.7 g of 4-trityloxy-butanal as white crystals of m.p. 62°-65° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].O>C(COC)OC.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>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:29]=[CH:30][C:31]([S:34][C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)=[CH:32][CH:33]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1
Reactant: Clc1ccc(Sc2ccc(Br)cc2)cc1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
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
Product: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(Sc3ccc(Cl)cc3)cc2)c1C
Yield: 37.9 %

Procedure:
A stirred solution of [6-fluoro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.2 g, 0.55 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.032 g, 0.028 mmol), impure 1-bromo-4-(4-chlorophenylsulfanyl)-benzene (0.25 g) and 1.0 M aqueous sodium bicarbonate (5 mL, 5 mmol) were added simultaneously to the reaction mixture under argon. The reaction mixture was refluxed for 2 hours and then brought to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (0-3% ethyl acetate in hexanes) to give {4-[4-(4-chloro-phenylsulfanyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.094 g, 37%) as a solid. MS calcd. for C26H21ClFO2S [(M+H)+] 451, obsd. 451.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1.[H-].[Na+].Cl.[CH:18](OCC)=[O:19]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9](=[CH:18][OH:19])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:7][CH:8]=1
Reactant: CCOC(=O)Cc1ccc(OC)cc1
Reactant: CCOC=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(=CO)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
8.9 ml of ethyl p-methoxyphenylacetate are dissolved in 80 ml of ethyl formate. 4.6 g of 50% NaH are added portionwise and then the mixture is stirred at ambient temperature for 12 hours. It is poured onto a 1N HCl solution and then extraction is carried out with AcOEt. Purification is carried out by chromatography on a silica column eluted with an AcOEt/heptane (05/95; v/v) mixture to produce 4.0 g of the expected compound in the liquid form.