Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].II.Br[CH2:5][C:6]([CH3:9])([CH3:8])[CH3:7].C([SiH:14]([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])CCC>C1COCC1>[CH:15]([SiH:14]([CH:18]([CH3:20])[CH3:19])[CH2:5][C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:17])[CH3:16]
Reactant: CC(C)(C)CBr
Reactant: CCCC[SiH](C(C)C)C(C)C
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)[SiH](CC(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Magnesium (2.43 g, 100 mmol) and iodine (catalytic amount) were added to THF (100 mL), and 1-bromo-2,2-dimethylpropane (10.7 mL, 100 mmol) was added dropwise thereto for 20 minutes, followed by stirring at room temperature for 1 hour. After termination of exothermic reaction, the resultant mixture was further stirred at 50° C. for 5 hours, whereby 2,2-dimethylpropylmagnesium bromide THF solution was prepared. The procedure of synthesizing Compound 47a was repeated, except that the thus-prepared mixture was employed, whereby the Compound 51a was obtained as a colorless liquid (boiling point; 40 mmHg, 120.0 to 122.5° C. fraction, 7.65 g, 45%).
Reaction SMILES: [C@@H:1]1([N:10]2[CH:18]=[C:16]([CH3:17])[C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:7][C@H:6]([CH2:8][OH:9])[C@H:4]([OH:5])[C@H:2]1[OH:3]>O.[Rh]>[CH3:17][CH:16]1[CH2:18][N:10]([C@@H:1]2[O:7][C@H:6]([CH2:8][OH:9])[C@H:4]([OH:5])[C@H:2]2[OH:3])[C:11](=[O:12])[NH:13][CH:14]1[OH:15].[CH3:17][CH:16]1[CH2:18][N:10]([C@@H:1]2[O:7][C@H:6]([CH2:8][OH:9])[C@H:4]([OH:5])[C@H:2]2[OH:3])[C:11](=[O:12])[NH:13][CH2:14]1
Reactant: Cc1cn([C@@H]2O[C@H](CO)[C@H](O)[C@H]2O)c(=O)[nH]c1=O
Agent: [Rh]
Solvent: O
Product: CC1CN([C@@H]2O[C@H](CO)[C@H](O)[C@H]2O)C(=O)NC1O
Product: CC1CNC(=O)N([C@@H]2O[C@H](CO)[C@H](O)[C@H]2O)C1

Procedure:
In the manner given in Example 2D, 1-β-D-xylofuranosylthymine [Fox et al., J. Am. Chem. Soc. 80, 5155 (1958)] was hydrogenated in ammoniacal water in the presence of a rhodium on alumina catalyst to give 5-methyl-4-hydroxy-1-β-D-xylofuranosyl-tetrahydro-2(1H)-pyrimidinone and 5-methyl-1-β-D-xylofuranosyl-tetrahydro-2(1H)-pyrimidinone.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[CH3:7][CH:8]1[CH2:12][O:11][S@@:10](=[O:13])[N:9]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C(OCC)(=[O:22])C>O.C(#N)C.[Ru](Cl)(Cl)Cl>[CH3:7][C@@H:8]1[CH2:12][O:11][S:10](=[O:22])(=[O:13])[N:9]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: CC1CO[S@@](=O)N1c1ccccn1
Reactant: CCOC(C)=O
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: O
Product: C[C@@H]1COS(=O)(=O)N1c1ccccn1

Procedure:
A solution of sodium periodate (21 g, 0.10 moles) in water (150 ml) was added slowly to a solution of (R)-4methyl-3-pyridin-2-yl-[1,2,3]oxathiazolidine-2-oxide (15.4 g, 0.78 moles) and ruthenium(III)chloride (20 mg) in acetonitrile (1540 ml) whilst the temperature was kept below 5° C. A heavy precipitate developed. The mixture was poured into a mixture of ethyl acetate (500 ml) and water (500 ml) and then shaken. The organic phase was retained and the aqueous phase was extracted with further ethyl acetate (2×500 ml). The organic phases were combined, backwashed with water (500 ml), dried (MgSO4) and then evaporated in vacuo to give (R)-4-methyl-3-(2-pyridyl)-[1,2,3]-oxathiazolidine-2,2-dioxide (15.5 g) as a yellow oil.
Reaction SMILES: [CH2:1]([P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])P(=O)(OCC)OCC.[H-].[Na+].[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25]1[O:26][C:27]([CH3:56])=[C:28]([CH2:30][O:31][C:32]2[CH:53]=[CH:52][C:35]([CH2:36][N:37]([CH3:51])[C:38]3[C:42]([CH:43]=O)=[CH:41][N:40]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[N:39]=3)=[CH:34][C:33]=2[O:54][CH3:55])[N:29]=1.O>CN(C)C=O>[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25]1[O:26][C:27]([CH3:56])=[C:28]([CH2:30][O:31][C:32]2[CH:53]=[CH:52][C:35]([CH2:36][N:37]([CH3:51])[C:38]3[C:42](/[CH:43]=[CH:1]/[P:10](=[O:17])([O:11][CH2:12][CH3:13])[O:14][CH2:15][CH3:16])=[CH:41][N:40]([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)[N:39]=3)=[CH:34][C:33]=2[O:54][CH3:55])[N:29]=1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: COc1cc(CN(C)c2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1N(C)Cc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1)OCC
Reaction time: 0.5 h
Yield: 66.9 %

Procedure:
To a solution of tetraethyl methylenediphosphonate (63 mg) in N,N-dimethylformamide (3 mL) was added sodium hydride (60% in oil, 8.8 mg) at room temperature, and the mixture was stirred for 30 min. To the reaction mixture was added 3-([4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl](methyl)amino)-1-phenyl-1H-pyrazole-4-carbaldehyde (100 mg) and the mixture was further stirred at room temperature for 2 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to flash silica gel column chromatography and eluted with ethyl acetate-hexane (1:1 to 4:1, v/v) to give diethyl ((E)-2-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)(methyl)amino]-1-phenyl-1H-pyrazol-4-yl}ethenyl)phosphonate as a colorless oil (84.9 mg, yield 67%).
Reaction SMILES: O[C:2]1([C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][O:30][C:24]=3[CH:23]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:3]1[C:17]([O:19][CH2:20][CH3:21])=[O:18].C([SiH](CC)CC)C.B(F)(F)F.CCOCC.Cl>C(Cl)Cl>[CH2:29]1[O:28][C:25]2[CH:26]=[CH:27][C:22]([CH:2]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[C:4]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)=[C:3]3[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:23][C:24]=2[O:30]1
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccccc2C1(O)c1ccc2c(c1)OCO2
Agent: CC[SiH](CC)CC
Agent: Cl
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)C1=C(c2ccccc2)c2ccccc2C1c1ccc2c(c1)OCO2
Reaction time: 0.25 h
Yield: 100.8 %

Procedure:
To a solution of ethyl(1RS)-1-hydroxy-1-(3,4-methylenedioxyphenyl)-3-phenylindene-2-carboxylate (1.03 g, 2.58 mmol) in CH2Cl2 (40 mL) was added triethylsilane (0.49 ml, 3.07 mmol), followed by boron trifluoride etherate (1.55 ml, 12.6 mmol). The reaction mixture was allowed to stir for 15 min, at which time was added slowly 3M HCl. The mixture was extracted with EtOAc. The organic extract was washed successively with H2O, 5% aqueous NaHCO3 and saturated aqueous NaCl. The solvent was removed in vacuo to provide the title compound (1.00 g, 100%) as a mixture of Δ1 and Δ2 double bond isomers.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[C:17]3[C:12](=[CH:13][C:14]([CH2:18][CH2:19][C:20](O)=[O:21])=[CH:15][CH:16]=3)[CH2:11][CH2:10][C:9]2=[O:23])=[CH:5][CH:4]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[Cl:49][C:50]1[CH:51]=[C:52]([NH:57]/[C:58](/[NH2:61])=[N:59]/O)[CH:53]=[CH:54][C:55]=1[Cl:56].S([O-])([O-])(=O)=O.[Na+].[Na+]>CN(C=O)C>[Cl:49][C:50]1[CH:51]=[C:52]([NH:57][C:58]2[N:61]=[C:20]([CH2:19][CH2:18][C:14]3[CH:13]=[C:12]4[C:17](=[CH:16][CH:15]=3)[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:25][CH:24]=3)[C:9](=[O:23])[CH2:10][CH2:11]4)[O:21][N:59]=2)[CH:53]=[CH:54][C:55]=1[Cl:56]
Reactant: COc1ccc(CN2C(=O)CCc3cc(CCC(=O)O)ccc32)cc1
Reactant: N/C(=N\O)Nc1ccc(Cl)c(Cl)c1
Agent: O=S(=O)([O-])[O-]
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COc1ccc(CN2C(=O)CCc3cc(CCc4nc(Nc5ccc(Cl)c(Cl)c5)no4)ccc32)cc1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 19.5 %

Procedure:
To a solution of 3-(1-(4-methoxybenzyl)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)propanoic acid (200 mg, 0.589 mmol) in DMF (3 mL) were added HOBT (99 mg, 0.648 mmol), EDC (124 mg, 0.648 mmol), and DIPEA (0.154 mL, 0.884 mmol). The reaction mixture was stirred for 30 minutes, then (E)-1-(3,4-dichlorophenyl)-2-hydroxyguanidine (130 mg, 0.589 mmol) was added followed by sodium sulfate (419 mg, 2.95 mmol). The reaction mixture was heated at 110° C. for 12 h, then concentrated, diluted with water, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography on silica gel using 10-100% EtOAc/hexane to give 6-(2-(3-((3,4-dichlorophenyl)amino)-1,2,4-oxadiazol-5-yl)ethyl)-1-(4-methoxybenzyl)-3,4-dihydroquinolin-2(1H)-one as a yellow solid (0.06 g, 11% yield). 1H NMR 400 MHz, DMSO-d6: δ 2.65-2.68 (m, 2H), 2.90 (t, J=15.20 Hz, 2H), 2.95 (t, J=12.40 Hz, 2H), 3.16 (t, J=15.20 Hz, 2H), 3.70 (s, 3H), 5.05 (s, 2H), 6.84-6.90 (m, 3H), 7.02-7.04 (m, 1H), 7.14-7.16 (m, 3H), 7.38-7.41 (m, 1H), 7.57 (d, J=8.80 Hz, 1H), 7.69 (s, 1H), 10.23 (s, 1H). LCMS (ES-API), RT: 2.20 min; m/z 523.0 [M−H]−.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[O:17])[CH:11]=1)(=O)=O.FC(F)(F)C(O)=O.[CH3:25][C:26]1[S:27][CH:28]=[C:29]([C:31]([N:33]2[CH2:38][C:37]3([CH2:43][CH2:42][NH:41][CH2:40][CH2:39]3)[O:36][CH2:35][CH2:34]2)=[O:32])[N:30]=1.C(N(CC)CC)C>C(#N)C>[CH3:25][C:26]1[S:27][CH:28]=[C:29]([C:31]([N:33]2[CH2:38][C:37]3([CH2:43][CH2:42][N:41]([CH2:6][CH2:7][CH2:8][O:9][C:10]4[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=4)[CH:16]=[O:17])[CH2:40][CH2:39]3)[O:36][CH2:35][CH2:34]2)=[O:32])[N:30]=1
Reactant: Cc1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Reactant: CS(=O)(=O)OCCCOc1cccc(C=O)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(C(=O)N2CCOC3(CCN(CCCOc4cccc(C=O)c4)CC3)C2)cs1

Procedure:
A solution of 3-(3-formylphenoxy)propyl methanesulfonate (example 95, step a) (0.209 g) and (2-methylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate (example 4, step h) (0.32 g) and triethylamine (0.282 mL) in acetonitrile (10 mL) were heated at 65° C. for 18 hours. The solvent was evaporated off under reduced pressure and the residue partitioned between ethyl acetate and brine. The organic layer was dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography using 2% methanol and 1% triethylamine in dichloromethane. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.157 g.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:13][C:14]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]3[CH:39]=[CH:38][C:28]([CH2:29][P:30](=[O:37])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])=[CH:27][CH:26]=3)[N:15]=2)=[C:6]2[C:10]=1[CH2:9][N:8]([CH3:11])[C:7]2=[O:12].CC1(C)C(C)(C)OB([C:48]2[CH:49]=[N:50][N:51]([CH2:53][CH2:54][CH2:55][OH:56])[CH:52]=2)O1>>[OH:56][CH2:55][CH2:54][CH2:53][N:51]1[CH:52]=[C:48]([C:2]2[CH:3]=[CH:4][C:5]([NH:13][C:14]3[C:19]([C:20]([F:21])([F:22])[F:23])=[CH:18][N:17]=[C:16]([NH:24][C:25]4[CH:39]=[CH:38][C:28]([CH2:29][P:30](=[O:37])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])=[CH:27][CH:26]=4)[N:15]=3)=[C:6]3[C:10]=2[CH2:9][N:8]([CH3:11])[C:7]3=[O:12])[CH:49]=[N:50]1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)c4c3C(=O)N(C)C4)n2)cc1)OCC
Reactant: CC1(C)OB(c2cnn(CCCO)c2)OC1(C)C
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)cc1)OCC

Procedure:
The title compound was prepared according to the procedure for Example 97 using diethyl [4-({4-[(7-bromo-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzyl]phosphonate and 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propan-1-ol (WO2008/001076). 1H NMR (400 MHz, DMSO-d6) δ ppm: 10.74 (br s, 1H), 9.93 (s, 1H), 8.47 (s, 1H), 8.40-9.11 (m, 1H), 8.24 (s, 1H), 7.96 (s, 1H), 7.77 (d, J=8.6 Hz, 1H), 7.46-7.62 (m, 2H), 7.30 (d, J=6.8 Hz, 2H), 4.64 (s, 2H), 4.22 (t, J=7.1 Hz, 2H), 3.97 (quin, J=7.2 Hz, 4H), 3.43 (q, J=6.1 Hz, 2H), 3.26 (d, J=22.0 Hz, 2H), 3.12 (s, 3H), 1.97 (qd, J=6.7, 6.6 Hz, 2H), 1.16 (t, J=6.9 Hz, 6H). MS (ES+): m/z 674.22 [MH+]. HPLC: tR=1.39 min (UPLC TOF, polar—3 min).
Reaction SMILES: [NH2:1][CH:2]1[C:13](=[O:14])[N:4]2[C:5]([C:10]([OH:12])=[O:11])=[C:6]([Cl:9])[CH2:7][S:8][C@H:3]12.[S:15]([CH:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20](Cl)=[O:21])([OH:18])(=[O:17])=[O:16].C(=O)(O)[O-].[Na+]>CC(C)=O.O>[S:15]([CH:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20]([NH:1][CH:2]1[C:13](=[O:14])[N:4]2[C:5]([C:10]([OH:12])=[O:11])=[C:6]([Cl:9])[CH2:7][S:8][C@H:3]12)=[O:21])([OH:18])(=[O:17])=[O:16]
Reactant: NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12
Reactant: O=C(Cl)C(c1ccccc1)S(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)C1=C(Cl)CS[C@@H]2C(NC(=O)C(c3ccccc3)S(=O)(=O)O)C(=O)N12

Procedure:
The α-sulfo-acylamido-3-halo-cephem compounds of the Formula I wherein Q is a sulfo group (--SO3H) are prepared by following the acylation procedures employed for the preparation of α-sulfobenzylpenicillins described by U.S. Pat. No. 3,660,379 and in the J. Med. Chem., 15 (11), 11-5 (1972); ibid, p. 1108. For example, 7-amino-3-chloro-3-cephem-4-carboxylic acid is reacted with α-sulfophenylacetyl chloride in a mixture of acetone and water containing an excess of sodium bicarbonate to yield 7-(α-sulfophenylacetamido)-3-chloro-3-cephem-4-carboxylic acid. Examples of α-sulfoacylamido-3-halo-cephems of the present invention are,
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[F:23])=[N:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:24][CH3:25].[SH:26][C:27]1[N:31]([CH3:32])[N:30]=[N:29][N:28]=1>>[ClH:22].[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:9]2[C:8]3[C:13](=[CH:14][C:5]([O:4][CH2:3][CH2:2][S:26][C:27]4[N:31]([CH3:32])[N:30]=[N:29][N:28]=4)=[C:6]([O:24][CH3:25])[CH:7]=3)[N:12]=[CH:11][N:10]=2)=[C:17]([F:23])[CH:18]=1
Reactant: Cn1nnnc1S
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCBr
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCSc1nnnn1C
Product: Cl
Yield: 87.2 %

Procedure:
Using an analogous procedure to that described in Example 51, 7-(2-bromoethoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline (98 mg, 0.23 mmol), (prepared as described for the starting material in Example 51), was treated with 5-mercapto-1-methyltetrazole (40 mg, 0.35 mmol) to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(1-methyltetrazol-5-ylthio)ethoxy)-quinazoline hydrochloride (50 mg, 44%).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[C:32]([O:36][C:37](=[O:45])[NH:38][C@H:39]1[CH2:44][CH2:43][CH2:42][NH:41][CH2:40]1)([CH3:35])([CH3:34])[CH3:33]>>[C:32]([O:36][C:37](=[O:45])[NH:38][CH:39]1[CH2:44][CH2:43][CH2:42][N:41]([C:20]2[S:21][C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:26]=[CH:27][C:2]([Cl:1])=[CH:3][C:4]=3[C:28]([F:30])([F:31])[F:29])[N:8]=[CH:9]4)[C:18](=[O:25])[N:19]=2)[CH2:40]1)([CH3:35])([CH3:33])[CH3:34].[NH2:38][C@H:39]1[CH2:44][CH2:43][CH2:42][N:41]([C:20]2[S:21][C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:26]=[CH:27][C:2]([Cl:1])=[CH:3][C:4]=3[C:28]([F:29])([F:31])[F:30])[N:8]=[CH:9]4)[C:18](=[O:25])[N:19]=2)[CH2:40]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CC(C)(C)OC(=O)NC1CCCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)C1
Product: N[C@H]1CCCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)C1

Procedure:
(1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidin-3-yl)-carbamic acid tert-butyl ester was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and piperidin-3-(S)-yl-carbamic acid tert-butyl ester following General Procedure C. The compound was used directly following General Procedure H to provide 2-(3-(S)-Amino-piperidin-1-yl)-5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.N1C=CN=C1.[C:15]([Si:19](Cl)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:18])([CH3:17])[CH3:16]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[O:9][Si:19]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Oc1cc(F)cc(Br)c1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](Oc1cc(F)cc(Br)c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58 %

Procedure:
To a solution of 3-bromo-5-fluorophenol (5.7 g, 30 mmol), prepared as described in Procedure 3, and imidazole (4.0 g, 60 mmol, 2 eq) in anhydrous THF (100 mL) at 0° C. was added tert-butyldiphenyl-silyl chloride (9.6 mL, 1.3 eq). The resulting mixture was stirred at room temperature for 18 h. The reaction mixture was quenched with water and extracted with hexane/EtOAc (1:1). The combined organic layers were washed with H2O (2×) and sat. NaCl (2×), dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexanes/EtOAc) to give (3-bromo-5-fluorophenoxy)(tert-butyl)diphenylsilane as colorless oil (7.5 g, yield 58%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.[CH3:12][O-:13].[Na+].O>CO>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([O:13][CH3:12])=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ncc(Br)cc1[N+](=O)[O-]
Temperature: 20 °C

Procedure:
To a suspension of 5-bromo-2-chloro-3-nitropyridine (75.0 g, 1 wt, 1 eq) in methanol (300 mL, 4 vols), is added a solution of sodium methoxide in methanol (25 wt %, 88.6 g, 1.3 eq) over approximately 1 hour so as to maintain the internal temperature at 20±5° C. The mixture is stirred at 20° C. for at least 0.5 hr, then monitored for completion by HPLC. Water (375 mL, 5 vols) is then added to the mixture at such a rate as to maintain the internal temperature below 30° C., then aged at this temperature for at least 0.5 hr. The batch is then concentrated to 6 vols in vacuo. The resulting slurry is allowed to cool to 20-25° C., then collected by vacuum filtration, washed with water and dried in vacuo with a nitrogen bleed at 20-25° C. to constant weight to afford 5-bromo-2-methoxy-3-nitropyridine as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[F:9][C:10]1[CH:11]=[C:12]([OH:19])[CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17].C(N(C(C)C)CC)(C)C>CN1CCCC1=O>[Cl:8][C:4]1[CH:5]=[C:6]([O:19][C:12]2[CH:13]=[CH:14][C:15]([N+:16]([O-:18])=[O:17])=[C:10]([F:9])[CH:11]=2)[N:7]=[CH:2][N:3]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: Clc1ccnc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc(Oc2cc(Cl)ncn2)cc1F
Temperature: 50 °C
Reaction time: 13 h
Yield: 28.8 %

Procedure:
After dissolving 2,6-dichloropyrimidine (5.0 g) and 3-fluoro-4-nitrophenol (6.11 g) in 1-methyl-2-pyrrolidinone (25 ml) at room temperature under a nitrogen atmosphere, diisopropylethylamine (6.81 ml) was added and the mixture was stirred for 13 hours at 50° C. The reaction mixture was cooled to room temperature and then partitioned between ethyl acetate and water. The separated organic layer was washed with water, 1N aqueous sodium hydroxide, water, 10% aqueous potassium hydrogen sulfate and brine in that order and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and then ethyl acetate (25 ml) was added to the residue to precipitate crystals. The crystals were filtered and subjected to aeration drying to provide the title compound (2.61 g, 30%) as white crystals. The filtrate was concentrated under reduced pressure, and then diethyl ether (30 ml) was added to the resultant residue and the mixture was stirred. The precipitated crystals were filtered, washed with diethyl ether (5 ml×2) and subjected to aeration drying to provide the title compound (3.98 g, 44%) as white crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.C1COCC1.[CH2:21]([Mg]Br)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH2:21]([C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[N:6][CH:7]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCC[Mg]Br
Reactant: COc1ccc(-c2ccc(Br)cn2)cc1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCc1ccc(-c2ccc(OC)cc2)nc1

Procedure:
To a flask containing 13A (1 g) and dichloro[1,3-bis (diphenylphosphino)propane]nickle(II) (15 mg, prepared as in Kumada et al., Org. Syn. Coll. Vol. VI, p 407) is added THF (11 ml) and octyl magnesium bromide (2M, 2.74 ml). The solution is refluxed for 16 hrs, then poured into water and extracted three times with ethyl acetate. The combined organic layers are washed with brine and dried over sodium sulfate, and the solvent is removed in vacuo.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([S:11]([NH:14][C:15]3[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:22])(=[O:13])=[O:12])[N:10]=[C:4]2[N:3]=1.[Br:23]N1C(=O)CCC1=O>C(O)(=O)C.C(OC(=O)C)(=O)C>[Br:23][C:7]1[C:2]([CH3:1])=[N:3][C:4]2[N:5]([N:8]=[C:9]([S:11]([NH:14][C:15]3[C:16]([Cl:22])=[CH:17][CH:18]=[CH:19][C:20]=3[Cl:21])(=[O:13])=[O:12])[N:10]=2)[CH:6]=1
Reactant: Cc1ccn2nc(S(=O)(=O)Nc3c(Cl)cccc3Cl)nc2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: Cc1nc2nc(S(=O)(=O)Nc3c(Cl)cccc3Cl)nn2cc1Br
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
A suspension of 4.0 g (11 mmol) of 5-methyl-N-(2,6-dichlorophenyl)-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonamide in 50 ml of glacial acetic acid and 10 ml of acetic anhydride was stirred at 90° C. for 30 minutes. N-Bromosuccinimide (2.4 g, 13 mmol) was added to this hot solution, and the reaction mixture was stirred at 90° C. for 60 minutes. The solution was cooled and poured into 200 ml of ice water. A solid which separated was collected and dried. This crude product was purified by dissolving the sample in methylene chloride, filtering the solution through silica gel and triturating the fitrate with pentane. The desired product was obtained as a solid, mp 215°-216° C. IR and 1H NMR spectra were in agreement with the assigned structure.