Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH:22]=[CH:21][C:20]([CH2:23][N:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)=[CH:19][CH:18]=4)=[CH:16][C:9]=23)[C:5]([C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)=[N:4]1)[CH3:2].C(N(CC)CC)C.[C:44](Cl)(=[O:49])[C:45]([CH3:48])([CH3:47])[CH3:46]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH:22]=[CH:21][C:20]([CH2:23][N:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)=[CH:19][CH:18]=4)=[CH:16][C:9]=23)[C:5]([C:30]2[CH:35]=[CH:34][C:33]([NH:36][C:44](=[O:49])[C:45]([CH3:48])([CH3:47])[CH3:46])=[CH:32][CH:31]=2)=[N:4]1)[CH3:2]
Reactant: CCn1cc(-c2ccnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)cc23)c(-c2ccc(N)cc2)n1
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCn1cc(-c2ccnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)cc23)c(-c2ccc(NC(=O)C(C)(C)C)cc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
A solution of [4-(1-ethyl-4-{2-[4-(4-morpholinylmethyl)phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)phenyl]amine (0.104 mmol) in methylene chloride (5 mL) was treated with triethylamine (0.3 mmol), DMAP (0.01 mmol) and pivalyl chloride (0.15 mmol). The reaction was stirred for 3 h at room temperature and concentrated. The residue was dissolved in ethyl acetate (10 mL) and washed with water (2×5 mL). The organic layer was concentrated and the residue purified by Gilson reverse phase HPLC to provide the title product as a white powder (82%). ESMS [M+H]+: 563.2
Reaction SMILES: [CH:1]([N:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:14]3[N:15]=[N:16][N:17]([C:20]4[C:21]([F:26])=[N:22][CH:23]=[CH:24][CH:25]=4)[C:18]=3[CH3:19])[CH:10]=2)[C:5]1=[O:27])([CH3:3])[CH3:2].[H][H]>[C].[Pd].C(O)C>[CH:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:14]3[N:15]=[N:16][N:17]([C:20]4[C:21]([F:26])=[N:22][CH:23]=[CH:24][CH:25]=4)[C:18]=3[CH3:19])[CH:10]=2)[C:5]1=[O:27])([CH3:3])[CH3:2]
Reactant: Cc1c(-c2ccc3c(=O)n(C(C)C)ccc3c2)nnn1-c1cccnc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1c(-c2ccc3c(c2)CCN(C(C)C)C3=O)nnn1-c1cccnc1F
Yield: 69.6 %

Procedure:
30 mg of palladium carbon was added to 10 ml of ethanol solution with 10 mg of 4-(2-isopropyl-1-oxo-isoquinoline-6-yl)-1-(2-fluoropyridine-3-yl)-5-methyl-1H-[1,2,3]triazole, and hydrogen was added under 4 atm of hydrogen pressure. 8 hours later, the reaction solution was filtrated and after distilling out the solvents of the filtrate under reduced pressure, the residues were separated and purified by thin-layer chromatography (chloroform/methanol=10/1) to obtain 7 mg of the above compound as a white solid.
Reaction SMILES: Cl[CH:2]([C:7]1[CH:8]=[C:9]([C:23]2[N:28]=[C:27]([CH3:29])[N:26]=[C:25]([N:30]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)[CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)[N:24]=2)[C:10]([NH:13][C:14]2[CH:15]=[N:16][C:17]([O:21][CH3:22])=[C:18]([F:20])[CH:19]=2)=[N:11][CH:12]=1)[C:3]([F:6])([F:5])[F:4].[C:49]([N:56]1[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1)([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50].C(N(CC)CC)C>CC#N>[CH3:48][O:47][C:44]1[CH:43]=[CH:42][C:41]([CH2:40][N:30]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=2)[C:25]2[N:26]=[C:27]([CH3:29])[N:28]=[C:23]([C:9]3[CH:8]=[C:7]([CH:2]([N:59]4[CH2:58][CH2:57][N:56]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:61][CH2:60]4)[C:3]([F:4])([F:6])[F:5])[CH:12]=[N:11][C:10]=3[NH:13][C:14]3[CH:15]=[N:16][C:17]([O:21][CH3:22])=[C:18]([F:20])[CH:19]=3)[N:24]=2)=[CH:46][CH:45]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(Cl)C(F)(F)F)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(N4CCN(C(=O)OC(C)(C)C)CC4)C(F)(F)F)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Temperature: 100 °C
Yield: 96.1 %

Procedure:
A solution of 4-(5-(1-chloro-2,2,2-trifluoroethyl)-2-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (1.059 g, 1.548 mmol) in CH3CN (10.00 mL) was treated with 1-N-Boc-piperazine (Aldrich, 0.577 g, 3.10 mmol) and triethylamine (1.079 mL, 7.74 mmol) and the mixture was heated at 100° C. for 3 h. The reaction mixture was concentrated and the crude product was adsorbed onto a plug of silica gel and chromatographed through a silica gel column (100% DCM to 5% MeOH (w/NH3 in DCM) to give tert-butyl 4-(1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-2,2,2-trifluoroethyl)piperazine-1-carboxylate (1.24 g, 1.487 mmol, 96% yield) as a brown foam. m/z (ESI, +ve ion) 834 (M+H)+.
Reaction SMILES: C([O:3][P:4]([O:8]CC)[O:5]CC)C.[C:11]([BH2:15])([O:13][CH3:14])=[O:12].[Si:16](I)([CH3:19])([CH3:18])[CH3:17]>CC#N>[P:4]([O:8][Si:16]([CH3:19])([CH3:18])[CH3:17])([O:5][Si:16]([CH3:19])([CH3:18])[CH3:17])[O:3][Si:16]([CH3:19])([CH3:18])[CH3:17].[C:11]([BH2:15])([O:13][CH3:14])=[O:12]
Reactant: C[Si](C)(C)I
Reactant: CCOP(OCC)OCC
Agent: BC(=O)OC
Solvent: CC#N
Product: C[Si](C)(C)OP(O[Si](C)(C)C)O[Si](C)(C)C

Procedure:
Triethylphosphite-carbomethoxyborane (4) (1.13 g, 4.75 mmol) and Me3SiI 2.70 ml, 18.97 mmol) were taken in anhydrous CH3CN (45 ml) under nitrogen atmosphere. Immediately, the mixture became brown. It was heated at reflux for 3 hours. During this time, the brown color completely disappeared, the mixture was cooled, and the solvent was removed under reduced pressure to give a yellow solid. 11B NMR(CDCl3): δ=15 ppm, br. s. , 0.2 ppm, br. s. , major and a multiplet at -39 ppm, very small amount.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.N1[CH:18]=[CH:17]N=C1.C(Cl)(=O)C.Cl.[NH2:24][CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32].P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>C(#N)C.O>[CH3:17][C:18]1[N:24]([CH:25]2[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]2=[O:32])[C:4](=[O:6])[C:3]2[C:2](=[CH:10][C:9]([N+:11]([O-:13])=[O:12])=[CH:8][CH:7]=2)[N:1]=1
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: NC1CCC(=O)NC1=O
Reactant: c1c[nH]cn1
Agent: Cl
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: CC(=O)Cl
Solvent: CC#N
Solvent: O
Product: Cc1nc2cc([N+](=O)[O-])ccc2c(=O)n1C1CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.2 %

Procedure:
To a stirred mixture of 2-amino-4-nitrobenzoic acid (5.0 g, 28 mmol) and imidazole (2.2 g, 33 mmol) in acetonitrile (50 mL), was added acetyl chloride (2.3 mL, 33 mmol) at room temperature. The mixture was stirred at room temperature overnight. To the mixture, was added 3-amino-piperidine-2,6-dione hydrogen chloride (4.5 g, 28 mmol), imidazole (4.1 g, 60 mmol) and triphenyl phosphite (8.7 mL, 33 mmol), and heated to reflux for 22 hours. To the mixture, was added water (60 mL). The suspension was filtered and washed with water (2×50 mL), ethyl acetate (2×50 mL), and water (50 mL) to give 3-(2-methyl-7-nitro-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as an off-white solid (4.8 g, 55% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, 5.69 min (95.4%); 1H NMR (DMSO-d6) δ 2.15-2.25 (m, 1H, CHH), 2.59-2.69 (m, 2H, 2CHH), 2.70 (s, 3H, CH3), 2.79-2.87 (m, 1H, CHH), 5.35 (dd, J=6, 12 Hz, 1H, NCH), 8.20-8.29 (m, 2H, Ar), 8.34 (d, J=2 Hz, 1H, Ar), 11.10 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.60, 23.53, 30.49, 56.85, 120.26, 121.58, 124.35, 128.30, 147.08, 151.30, 157.61, 159.52, 160.09, 172.48; LCMS: MH=317.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:9][CH3:10])/[CH:4]=[CH:5]/[N+:6]([O-:8])=[O:7].[CH2:11]([SH:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1CCCCC1.O>C1(C)C=CC=CC=1>[CH3:1][O:2][CH:3]([O:9][CH3:10])[CH:4]([S:18][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:5][N+:6]([O-:8])=[O:7]
Reactant: SCc1ccccc1
Reactant: COC(/C=C/[N+](=O)[O-])OC
Solvent: O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: COC(OC)C(C[N+](=O)[O-])SCc1ccccc1
Yield: 86 %

Procedure:
A solution of (1E)-3,3-dimethoxy-1-nitroprop-1-ene (3.03 g, prepared according to Terahedron 2002, 58, 5773-5778), benzylmercaptan (2.54 ml) and piperidine (0.25 ml) in toluene (20 ml) was stirred at room temperature for 48 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=0:100-20:80) to give the title compound (4.78 g, yield 86%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[C:16]([C:18]2[NH:19][C:20]([C:23]3[S:24][CH:25]=[CH:26][N:27]=3)=[CH:21][CH:22]=2)[CH:15]=[C:14]([O:28][C@@H:29]([CH3:33])[CH2:30][O:31][CH3:32])[CH:13]=1)[C:5]([OH:7])=O.N.CC[N:37]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl.O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[C:16]([C:18]2[NH:19][C:20]([C:23]3[S:24][CH:25]=[CH:26][N:27]=3)=[CH:21][CH:22]=2)[CH:15]=[C:14]([O:28][C@@H:29]([CH3:33])[CH2:30][O:31][CH3:32])[CH:13]=1)[C:5]([NH2:37])=[O:7]
Reactant: CCN=C=NCCCN(C)C
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)O)cc2F)cc(-c2ccc(-c3nccs3)[nH]2)c1
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(N)=O)cc2F)cc(-c2ccc(-c3nccs3)[nH]2)c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 23.7 %

Procedure:
3-Fluoro-4-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}benzoic acid (40.0 mg, 0.163 mmol) synthesized in Example (44a) was dissolved in dichloromethane (5 mL), and 28% aqueous ammonia solution (0.50 mL), WSCI.HCl (19.6 mg, 0.102 mmol) and HOBt.H2O (13.1 mg, 0.086 mmol) were added, followed by stirring at room temperature for 7 hours under nitrogen atmosphere. To the reaction solution, water (10 mL) was added, and extraction was carried out with ethyl acetate (20 mL). The organic layer was washed with saturated brine, and subsequently dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=0%-75%) to afford the desired compound (11.3 mg, yield 28%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.Cl.[F:11][C:12]([F:26])([F:25])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[Cl:8][C:6]1[CH:5]=[C:4]([N:22]2[CH2:23][CH2:24][CH:19]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]([F:11])([F:25])[F:26])[CH2:20][CH2:21]2)[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: FC(F)(F)c1ccccc1C1CCNCC1
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1nc(Cl)cc(N2CCC(c3ccccc3C(F)(F)F)CC2)n1
Temperature: 210 °C
Reaction time: 0.33 h
Yield: 117.7 %

Procedure:
2-Amino 4,6-dichloro pyrimidine (0.164 g, 1 mmol), 4-(2-trifluoromethyl-phenyl)-piperidine hydrochloride (0.266 g, 1 mmol), and cesium carbonate (0.684 g, 2.1 mmol) were dissolved in a mixture of 1,4-dioxane (5 ml) and H2O (5 ml) in a 20 ml microwave vial. The mixture was stirred at 210° C. for 20 minutes in a microwave reactor. Solvent was removed and the residue was dissolved in 5% methanol in CH2Cl2 (20 ml), dried over Na2SO4 and concentrated to get the crude intermediate, 4-chloro-6-[4-(2-trifluoromethyl-phenyl)-piperidin-1-yl]-pyrimidin-2-ylamine (0.42 g) which was directly used in the following step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:7][N:8]([CH3:10])[CH3:9])[S:5][CH:6]=1.C(NC(C)C)(C)C.[Li].[CH:19](N1CCCCC1)=[O:20]>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:7][N:8]([CH3:10])[CH3:9])[S:5][C:6]=1[CH:19]=[O:20]
Reactant: CN(C)Cc1cc(Br)cs1
Reactant: O=CN1CCCCC1
Agent: [Li]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CN(C)Cc1cc(Br)c(C=O)s1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To (4-bromo-thiophen-2-ylmethyl)-dimethyl-amine [4.08 g, 18.5 mmol, Intermediate (1)] in tetrahydrofuran (40 mL) at 0° C. and under a nitrogen atmosphere is added Lithium diisopropylamine (2.0M in tetrahydrofuran pentanes from Aldrich chemicals, 20.4 mmol). The orange solution is stirred at 0° C. for 30 minutes. Then N-formylpiperidine is added (2.5 mL, 22.2 mmol). The mixture is allowed to stir at 0° C. for 1 hour. It is diluted with ethyl acetate washed with brine, dried over magnesium sulfate and concentrated. The residual orange oil was chromatographed through silica gel (dichloromethane-1.0M ammonia in methanol, 95:05 as eluant) to produce 3-bromo-5-dimethylaminomethyl-thiophene-2-carbaldehyde [4.4 g, Intermediate (2)] as an orange oil. LC/MS: RT=0.47 minutes, 247.98 m/e (M+H).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:13]([N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])=[N:12][CH:11]=[C:10]([O:23][CH3:24])[C:9]=3[C:8]2=[O:25])=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:36])C=1.C(O)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:13]([N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])=[N+:12]([O-:36])[CH:11]=[C:10]([O:23][CH3:24])[C:9]=3[C:8]2=[O:25])=[CH:26][CH:27]=1
Reactant: COc1cnc(N(C)S(C)(=O)=O)c2c1C(=O)N(Cc1ccc(F)cc1)CC2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCO
Solvent: ClCCl
Product: COc1c[n+]([O-])c(N(C)S(C)(=O)=O)c2c1C(=O)N(Cc1ccc(F)cc1)CC2
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of N-[6-(4-fluorobenzyl)-4-methoxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl]-N-methylmethanesulfonamide (0.35 g, 0.89 mmol) in CH2Cl2 (10 mL) was added mCPBA (1.08 g, 6.23 mmol) in portions. After stirring for 3.5 hours at reflux, the product mixture was cooled to room temperature, 1 mL of ethanol was added, and the solution was concentrated. The residue was partitioned between CHCl3 and saturated Na2SO3. The organic layer was extracted repeatedly with saturated sodium bicarbonate. The organic extract was dried with Na2SO4, filtered, and concentrated under vacuum to provide the crude title compound.
Reaction SMILES: [OH-:1].[K+].[F:3][C:4]1[CH:9]=[C:8]([CH:10]([CH3:15])[C:11](OC)=[O:12])[CH:7]=[CH:6][C:5]=1[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[F:23].Cl.[NH2:25]O>CO.O>[F:3][C:4]1[CH:9]=[C:8]([CH:10]([CH3:15])[C:11]([NH:25][OH:1])=[O:12])[CH:7]=[CH:6][C:5]=1[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[F:23]
Reactant: [OH-]
Reactant: COC(=O)C(C)c1ccc(-c2ccc(F)cc2F)c(F)c1
Reactant: NO
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C(=O)NO)c1ccc(-c2ccc(F)cc2F)c(F)c1
Reaction time: 8 h

Procedure:
Potassium hydroxide (1.0 g.) in methanol (20 ml.) was added dropwise to a solution of methyl 2-(2,2',4'-trifluoro-4-biphenylyl)propionate (0.42 g.) and hydroxylamine hydrochloride (0.5 g.) in methanol (10 ml.) until the solution was just alkaline to limits. After standing overnight at room temperature the filtrate from inorganic salts was evaported to small bulk, diluted with water, washed with ether, acidified with dilute hydrochloric acid, re-extracted with ether, washed with ether, dried and evaporated to dryness. The residue was racrystallised from benzene to give 2-(2,2',4'-trifluoro-4-biphenylyl) propionhydroxamic acid, m.p. 148°-150° C. (decomp.)
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:25])[C@H:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:16]=[CH2:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([Si:29]([CH3:32])([CH3:31])[CH3:30])C=C.C(Cl)(Cl)Cl>C(Cl)Cl.Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:25])[C@H:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)/[CH:16]=[CH:17]/[CH2:26][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC[Si](C)(C)C
Reactant: C=C[C@@H](Cc1ccccc1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: C[Si](C)(C)C/C=C/[C@@H](Cc1ccccc1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1

Procedure:
To a solution of (4R)-4-benzyl-3-[(2R)-2-benzylbut-3-enoyl]-1,3-oxazolidin-2-one (3.42 mmol, 1.10 g) and allyltrimethylsilane (10.26 mmol, 1.63 mL) in DCM (50 mL) at reflux was added 5 mol % of Grubbs' second generation catalyst (145 mg). After 68 hrs the solvent was removed in vacuo. The crude product was purified by column chromatography to yield a white solid. (1.37 g, 95%); 1H NMR (400 MHz, CDCl3): δ=7.0-7.32 (m, 10H), 5.62 (dt, J=8.1, 15.2, 1H), 5.29-5.36 (m, 1H), 4.82 (m, 1H), 4.61 (m, 1H), 4.01-4.15 (m, 2H), 3.22 (dd, J=8.3, 13.4, 1H), 3.02 (dd, J=3.3, 13.3, 1H), 2.85 (dd, J=6.1, 13.4, 1H), 2.57 (dd, J=9.1, 13.4, 1H) 1.42 (d, J=8.1, 1H) −0.08 (s, 9H); 13C NMR (100 MHz, CDCl3): δ=174.2, 138.9, 135.1, 131.6, 129.4, 128.9, 128.3, 127.2, 126.3, 124.9, 65.7, 55.2, 48.2, 38.9, 37.6, 23.1, −2.1; IR (CHCl3): v 3444, 2955, 1767, 1694, 1454, 1393, 1248, 1182 cm−1; MS (CI(NH3)): m/z 422 (M+H+); HMRS required for C25H32NO3Si ([M]+) 422.2158 found 422.2151; [α]D23=117.8° (c, 0.5 CHCl3); Mp 132-135° C.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([OH:16])=O.O=S(Cl)Cl.Cl.[NH2:22][C:23]([NH2:25])=[NH:24]>[OH-].[Na+].C1COCC1>[ClH:13].[Cl:13][C:9]1[CH:8]=[C:7]([N:6]2[C:2]([CH3:1])=[C:3]([C:14]([NH:24][C:23]([NH2:25])=[NH:22])=[O:16])[CH:4]=[N:5]2)[CH:12]=[CH:11][CH:10]=1
Reactant: N=C(N)N
Reactant: Cc1c(C(=O)O)cnn1-c1cccc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Cc1c(C(=O)NC(=N)N)cnn1-c1cccc(Cl)c1
Yield: 12.7 %

Procedure:
A mixture of 5-methyl-1-(3-chlorophenyl)pyrazole-4-carboxylic acid (234 mg, 1.0 mmol) and 5 ml SOCl2 was heated to reflux for 45 min. Excess SOCl2 was removed in vacuo via codistillation with toluene. The residue was dissolved in 2mL of anhydrous THF and added dropwise over 30 minutes to a vigorously stirred 40° C. solution of guanidine hydrochloride (344 mg, 3.6 mol) in 3.25 mL 2 N NaOH and 1.9 mL THF. The resulting mixture was heated to reflux for 4 hours and then cooled. The organic solvent was removed in vacuo. The residue was diluted with 10 mL 1 N NaOH and extracted with 5×5 mL EtOAc. The combined organic layers were dried (Na2SO4) filtered and concentrated in vacuo to a white solid. This material was dissolved in 1 mL MeOH and 18.4 μL 12 N HCl was added with stirring. The solvents were removed in vacuo with toluene azeotropes and the resulting solid was stirred in 1 mL ether/acetone (1:1) and filtered to remove residual H2O. Drying under high vacuum at 40° C. afforded the desired product (20 mg, 6%).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:7]1[N:8]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[S:26](=[O:33])(=[O:32])[NH:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:16][CH:15]=2)[C:9](=[O:12])[NH:10][N:11]=1)[CH2:4][CH2:5][CH3:6].[CH:34](I)([CH3:36])[CH3:35].O>CN(C=O)C>[CH2:3]([C:7]1[N:8]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[S:26](=[O:32])(=[O:33])[NH:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:18][CH:19]=2)[C:9](=[O:12])[N:10]([CH:34]([CH3:36])[CH3:35])[N:11]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1n[nH]c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1nn(C(C)C)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.4 %

Procedure:
To a suspension of 54 mg (1.35 mmole) of sodium hydride (60% in oil) in 1 ml of dry DMF was added 200 mg (0.452 mmole) of 5-n-butyl-4-[[2'-(N-t-butylsulfamoyl)biphenyl-4-yl]methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (from Step G). The resulting mixture was stirred under N2 at room temperature for 2 hours. Then 270 μL (460 mg, 2.70 mmole) of isopropyl iodide was added dropwise, and the orange mixture was stirred at room temperature overnight. Next, the mixture was treated with H2O and extracted 4× with ethyl acetate. The combined organic fractions were washed with brine, dried over MgSO4, and filtered. The filtrate was concentrated in vacuo, and the residue was flash chromatographed twice on silica gel (elution with 1.5% MeOH in CH2Cl2) to yield 106 mg (48%) of the title compound; satisfactory purity by TLC in 98.5:1.5 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 485 (M+1)+.
Reaction SMILES: C(O[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([N:19]2[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20]2)=[C:16]([F:18])[CH:17]=1)=O)C1C=CC=CC=1.C([Li])CCC.[CH2:30]([O:34][C:35](=[O:39])CCC)[C@@H:31]1[O:33]C1.C(=O)(O)[O-].[Na+]>O1CCCC1.CN1CCCN(C)C1=O.C(OCC)(=O)C>[F:18][C:16]1[CH:17]=[C:12]([N:11]2[CH2:9][C@H:30]([CH2:31][OH:33])[O:34][C:35]2=[O:39])[CH:13]=[CH:14][C:15]=1[N:19]1[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20]1
Reactant: CCCC(=O)OC[C@H]1CO1
Reactant: Cc1cn(-c2ccc(NC(=O)OCc3ccccc3)cc2F)cn1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN1CCCN(C)C1=O
Product: Cc1cn(-c2ccc(N3C[C@H](CO)OC3=O)cc2F)cn1
Reaction time: 0.5 h
Yield: 33.7 %

Procedure:
5-Benzyloxycarbonylamino-2-(4-methylimidazol-1-yl)fluorobenzene (54 g, 0.166 M) was dissolved in a mixture of dry tetrahydrofuran (600 ml) and 1,3-dimethyl-2,4,5,6-tetrahydro-2(1H)-pyrimidinone (100 ml) under nitrogen, cooled to −70°, and treated with a solution of n-butyllithium (1.6 M in isohexane, 114 ml), over 30 minutes. After stirring for 30 minutes at −70°, a solution of (R)-glycidylbutyrate (26.35 g, 0.183 M) in dry tetrahydrofuran (50 ml) was added over 15 minutes. Stirring was continued for 16 hours allowing the temperature to rise to ambient. The mixture was treated with aqueous sodium bicarbonate (5%, 500 ml) and ethyl acetate (800 ml), and undissolved solid was removed and washed well with diethyl ether to give title product (16.3 g).
Reaction SMILES: [Cl:1][C:2]1[C:6]([C:7]#N)=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])[S:4][N:3]=1.S(=O)(=O)(O)[OH:17].N([O-])=O.[Na+].[OH2:25]>>[Cl:1][C:2]1[C:6]([C:7]([OH:17])=[O:25])=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])[S:4][N:3]=1
Reactant: Cc1ccccc1-c1snc(Cl)c1C#N
Reactant: O=S(=O)(O)O
Reactant: O
Agent: O=N[O-]
Agent: [Na+]
Product: Cc1ccccc1-c1snc(Cl)c1C(=O)O
Temperature: 120 °C
Reaction time: 1 h

Procedure:
Into a 100-mL round-bottom flask, was placed 3-chloro-5-(2-methylphenyl)-1,2-thiazole-4-carbonitrile (6 g, 25.56 mmol, 1.00 equiv). This was followed by the addition of sulfuric acid (8 mL). The mixture was stirred at 120° C. for 1 h. To this was added a solution of NaNO2 (3.54 g, 51.30 mmol, 2.01 equiv) in water (5 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 1 h at 50° C. in an oil bath. The resulting solution was extracted with 3×50 mL of ethyl acetate and the organic layers combined, washed with 20 mL 2N HCl, dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 5 g (crude) of 3-chloro-5-(2-methylphenyl)-1,2-thiazole-4-carboxylic acid as yellow oil.
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[N:4]=1.[CH3:10][C:11]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:12]=1[CH2:13][SH:14].[OH-:20].[Na+].O>CN(C=O)C>[CH3:10][C:11]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:12]=1[CH2:13][S:14][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[N+:4]=1[O-:20]
Reactant: Cc1cccc(Br)n1
Reactant: [OH-]
Reactant: Cc1ccc(C)c(CS)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C)c(CSc2cccc(C)[n+]2[O-])c1

Procedure:
A mixture of 4.48 g (0.020 mole) of 2-bromo-6-methylpyridine hydrochloride, 3.34 g (0.022 mole) of 2,5-dimethylbenzylmercaptan and 0.88 g (0.022 mole) of powdered sodium hydroxide were stirred together at room temperature in 35 ml of DMF for 3.5 hours. The reaction mixture was poured into water and the precipitate filtered off and washed with water. Yield 1.96 g or 38%.