Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[CH:3]([C:5]1([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]=2[CH3:21])[CH:10]=[CH:9][CH:8]=[CH:7][CH2:6]1)=[O:4].S([O-])([O-])=O.[Na+].[Na+]>ClCCl>[CH:3]([C:5]1([C:11]2[CH:20]=[C:19]([Br:1])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]=2[CH3:21])[CH:6]=[CH:7][CH:8]=[CH:9][CH2:10]1)=[O:4]
Reactant: BrBr
Reactant: Cc1c(C2(C=O)C=CC=CC2)ccc2ccccc12
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(C2(C=O)C=CC=CC2)cc(Br)c2ccccc12
Reaction time: 3 h

Procedure:
A mixture of 19.5 ml (380 mmol) of bromine and 300 ml of dichloromethane is added dropwise with exclusion of light to a solution, cooled to 0° C., of 86.2 g (350 mmol) of 2-(1-formylphenyl)-1-naphthylmethane in 1500 ml of dichloromethane. After stirring for a further 3 h, 1000 ml of 5% sodium sulfite solution are added, the mixture is stirred briefly, the organic phase is separated off, washed three times with 500 ml of water and evaporated in vacuo, and the residue is taken up in a little acetone. After standing for 24 h, the crystals are filtered off with suction, washed with acetone:n-hexane (1:1) and dried in vacuo. Yield: 90.7 g (279 mmol), 79.7%, purity about 98% (NMR).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[CH:31]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)=[O:32].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7]([C:6]1[CH:20]=[C:2]([C:37]2[CH:36]=[CH:35][CH:34]=[C:33]([CH:31]=[O:32])[CH:38]=2)[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21])=[O:8]
Reactant: CCN(c1cc(Br)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Reactant: O=Cc1cccc(B(O)O)c1
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: C1COCCO1
Product: CCN(c1cc(-c2cccc(C=O)c2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 100 °C
Yield: 64.1 %

Procedure:
To a stirred solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide (400 mg, 0.84 mmol) and (3-formylphenyl)boronic acid (189 mg, 1.26 mmol) in dioxane (2 mL), aqueous 2M Na2CO3 solution (1.5 mL, 3.03 mmol) was added and solution was purged with argon for 15 min. Then Pd(PPh3)4 (97 mg, 0.08 mmol) was added and argon was purged again for 15 min. Reaction mass was heated at 100° C. for 4 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM (3 times). Combined organic layer was dried over sodium sulphate. Removal of the solvent under reduced pressure followed by column chromatographic purification afforded the title compound (270 mg, 64%).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([NH:7][C:8]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[C:23]4[N:24]=[CH:25][N:26]([C@@H:27]5[O:31][C@H:30]([CH2:32][OH:33])[C@@H:29]([OH:34])[C@H:28]5[OH:35])[C:22]=4[N:21]=[CH:20][N:19]=3)=[CH:13][CH:12]=2)=[O:9])[CH:4]=[C:3]([CH2:36][C:37]([NH:39][CH2:40][CH2:41][NH2:42])=[O:38])[CH:2]=1.C(N(CC)CC)C.C(Cl)(Cl)=S.[Cl-:54].[Na+].CN(C)C=[O:59]>O>[CH:1]1[CH:6]=[C:5]([NH:7][C:8]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:18]3[C:23]4[N:24]=[CH:25][N:26]([C@@H:27]5[O:31][C@H:30]([CH2:32][OH:33])[C@@H:29]([OH:34])[C@H:28]5[OH:35])[C:22]=4[N:21]=[CH:20][N:19]=3)=[CH:15][CH:16]=2)=[O:9])[CH:4]=[C:3]([CH2:36][C:37]([NH:39][CH2:40][CH2:41][NH2:42])=[O:38])[CH:2]=1.[CH2:36]1[C:37](=[O:38])[N:39]([Cl:54])[C:40](=[O:59])[CH2:41]1
Reactant: [Cl-]
Reactant: CN(C)C=O
Agent: NCCNC(=O)Cc1cccc(NC(=O)Cc2ccc(Nc3ncnc4c3ncn4[C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)cc2)c1
Agent: S=C(Cl)Cl
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Product: O=C1CCC(=O)N1Cl

Procedure:
ADAC, 25 mg, 43 micromol, and 6 microliters triethylamine were dissolved in 1 ml dimethylformamide with warming. After cooling in an ice bath, 3.9 microl, 51 micromol of distilled thiophosgene was added with stirring. Water and saturated sodium chloride were added to obtain a white precipitate-, which was dried in vacuo over sodium hydroxide. The yield was 13 mg, or 48%, of product. IR peaks appeared at 3460, 2120, 1640, 1600, 1515, 1480, 1420, 1100, 1060, and 1030 cm-1. Thin layer chromatography and the Cf plasma desorption spectrum was consistent with the assigned structure and showed no evidence of residual ADAC.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)C(C)C)(C)C.CCOCC>C(OCC)(=O)C>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 65 °C
Reaction time: 120 h
Yield: 76.6 %

Procedure:
4-Fluoronitrobenzene (4.8 g, 34 mmol) was dissolved in ethyl acetate (25 mL). Piperazine-1-carboxylic acid tert-butyl ester (6.7 g, 36 mmol) and N,N-diisopropylethylamine (6.3 mL, 36 mmol) were added and the mixture was stirred at 65° C. for five days and cooled to room temperature. Ether (100 mL) was added and the combined mixture was washed with water (25 mL) and brine (25 mL), dried (Na2SO4), filtered and concentrated under vacuum. The residue was triturated with hexane to yield a bright yellow solid (8 g, 77%).
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][CH2:7][S:8][C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:4])=[O:3].[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][S:2]([O-:5])(=[O:4])=[O:3].[C:16]1([C:9]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[S:8][CH2:7][CH2:6][N+:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: c1ccncc1
Reactant: CS(=O)(=O)OCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Product: CS(=O)(=O)[O-]
Product: c1ccc(C(SCC[n+]2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 90 °C

Procedure:
A mixture of 2-(triphenylmethylthio)ethyl methanesulfonate (0.598 g, 1.50 mmol), tetra-n-butylammonium iodide (0.020 g) and pyridine. (1.2 mL, 15.0 mmol) was heated at 90° C. under a nitrogen atmosphere for 3 h. After cooling to 25° C., the pyridine was evaporated under reduced pressure to a white solid which was triturated in ether and filtered 0.66 g, (92%), mp 135°-50° C. dec. ir (KBr) νmax : 1628 (pyridinium), 1590, 1575 (phenyl), 1190 cm-1 (sulfonate), 1Hmr (DMSO-d6) δ: 2.31 (3H, s, CH3SO3-), 2.82 (2H, m, CH2S), 4.40 (2H, m, CH2N+), 7.28 (15H, m, phenyl), 8.12 (2H, m, Hm of pyridinium), 8.59 (1H, m, Hp of pyridinium), 8.84-8.85 (2H, dd, J=1.3 Hz, J=6.7 Hz, Ho of pyridinium). Anal. calcd. for C27H37NO3S2.H2O: C 65.43, H 5.90, N 2.83, S 12.94; found: C 65.77, H 5.81, N 3.25, S 12.55.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9](=[O:14])[CH:8]=[C:7]2[NH:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.[CH:22]([C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1)=O>>[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9](=[O:14])[CH:8]=[C:7]2[NH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:24]2[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=2)[CH2:18][CH2:17]1
Reactant: COc1ccc2oc(=O)cc(NC3CCNCC3)c2c1
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: Cl
Product: COc1ccc2oc(=O)cc(NC3CCN(Cc4ccc(C(=O)O)cc4)CC3)c2c1

Procedure:
According to Procedure C above, (I) (0.300 g of hydrochloride salt; 1.09 mmol) and 4-formyl-benzoic acid were allowed to react to afford after HPLC purification and precipitation with hydrochloric acid as described before, 0.182 g (35.4%) of the title compound. MS (DCI/NH3)(+)Q1MS m/z 409 (M+H)+; 1H NMR (500 MHz, pyridine-d5) δ ppm 1.78 (m, 2H), 2.13 (m, 4H), 2.89 (m, 2H), 3.42 (s, 3H), 3.56 (m, 1H), 3.57 (s, 2H), 5.72 (s, 1H), 7.15 (dd, J=9.05, 2.81 Hz, 1H), 7.34 (d, J=9.05 Hz, 1H), 7.53 (d, J=8.11 Hz, 2H), 7.62 (br d, J=7.18 Hz, N H), 7.70 (d, J=2.50 Hz, 1H) 8.41 (d, J=8.11 Hz, 2H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([C:14]([CH3:18])([CH3:17])[C:15]#[N:16])[CH:6]=[C:7]([C:9]([CH3:13])([CH3:12])[C:10]#[N:11])[CH:8]=1.[NH:19]1[CH:23]=[N:22][CH:21]=[N:20]1>C(#N)C>[N:19]1([CH2:2][C:3]2[CH:4]=[C:5]([C:14]([CH3:18])([CH3:17])[C:15]#[N:16])[CH:6]=[C:7]([C:9]([CH3:13])([CH3:12])[C:10]#[N:11])[CH:8]=2)[CH:23]=[N:22][CH:21]=[N:20]1
Reactant: CC(C)(C#N)c1cc(CCl)cc(C(C)(C)C#N)c1
Reactant: c1nc[nH]n1
Solvent: CC#N
Product: CC(C)(C#N)c1cc(Cn2cncn2)cc(C(C)(C)C#N)c1

Procedure:
A solution of 2,2'-(5-chloromethyl-1,3-phenylene)di(2-methylpropiononitrile), (0.23 g), and 1H-1,2,4-triazole (0.35 g) in acetonitrile (2 ml) was heated under reflux for 18 h, then evaporated to dryness. The residue was partitioned between 1N aqueous potassium hydrogen carbonate solution and ethyl acetate, the organic phase was separated, dried and evaporated to dryness under reduced pressure, and the residue was purified by flash column chromatography. Elution with methanol:chloroform (1:49 by volume), gave 2,2'-[5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]di(2-methylpropiononitrile), identical with the product of Example 1, and further elution with methanol:chloroform (2:23 by volume, gave 2,2'-[5-(4H-1,2,4-triazol-4-ylmethyl)-1,3-phenylene]di(2-methylpropiononitrile), mp. 158°-161°.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]2([C:38](C)(C)[O:39][SiH2]C(C)(C)C)[CH2:37][CH2:36][CH:35]=[CH:34][CH2:33]2)[NH:9]1)=[O:7])(C)(C)C.[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50]>ClCCl>[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50].[Cl:19][C:15]1[C:14]([F:20])=[C:13]([CH:12]2[C:11]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]3([CH2:38][OH:39])[CH2:37][CH2:36][CH:35]=[CH:34][CH2:33]3)[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)C1NC(CC2(C(C)(C)O[SiH2]C(C)(C)C)CC=CCC2)C(C#N)(c2ccc(Cl)cc2F)C1c1cccc(Cl)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CC1(c2ccc(Cl)cc2F)C(CC2(CO)CC=CCC2)NC(C(=O)O)C1c1cccc(Cl)c1F
Yield: 92 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-5-[1-(tert-butyl-dimethyl-silanyloxymethyl)-cyclohex-3-enylmethyl]-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 117b (2.6 g, 3.8 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-hydroxymethyl-cyclohex-3-enylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (2.2 g, 92%).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([OH:8])[CH:6]([OH:9])[CH:5]([CH2:10][O:11][P:12]([OH:15])([OH:14])=[O:13])[O:4][CH:3]1[CH2:16][CH2:17][CH2:18][O:19]C(=O)CCCCC.[OH-].[Na+:28].C([O-])(=O)C.[Na+]>O.C(O)C.C(OCC)C>[Na+:28].[OH:9][CH:6]1[CH:7]([OH:8])[CH:2]([OH:1])[CH:3]([CH2:16][CH2:17][CH2:18][OH:19])[O:4][CH:5]1[CH2:10][O:11][P:12](=[O:13])([OH:14])[O-:15]
Reactant: CCCCCC(=O)OCCCC1OC(COP(=O)(O)O)C(O)C(O)C1O
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: O=P([O-])(O)OCC1OC(CCCO)C(O)C(O)C1O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 63 %

Procedure:
Hexanoic acid 3-(3,4,5-trihydroxy-6-phosphonooxymethyl-tetrahydro-pyran-2-yl)-propyl ester (2.1 g, 5.25 mmol) (prepared in Example 8) was dissolved in water (50 ml) and aqueous sodium hydroxide (1M, 4 eq, 12 ml) was added and stirred for 40 minutes at room temperature after which the solution was acidified (pH˜2) with Dowex 50W X8 H+ form. The solution was washed with dichloromethane (2×100 ml) and the solvent was removed. The residue was then dissolved in a minimum of water and added dropwise to a solution of sodium acetate (1.2 eq, 0.34 g) in ethanol (150 ml) and diethyl ether (50 ml). The resulting precipitate was centrifuged and the ethanol decanted off, the residue was washed with diethyl ether (2×100 ml) and dried to give phosphoric acid mono-[3,4,5-trihydroxy-6-(3-hydroxy-propyl)-tetrahydro-pyran-2-ylmethyl] ester monosodium salt (1.01 g, 63%). 1Hnmr (500 MHz, D2O): δ 1.35-1.46 (m, 2H), 1.46-1.58 (m, 1H), 1.62-1.72 (m, 1H), 3.41-3.50 (m, 3H) 3.56 (t, J=9.0 Hz, 1H), 3.65-3.70 (m, 1H), 3.71-3.79 (m, 2H), 3.83-3.96 (m, 2H); ESMS (−ve) 301 (M−H).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Br:11][C:12]1[N:13]([CH2:25][CH:26]=[C:27]([CH3:29])[CH3:28])[C:14]([C:21]([O:23][CH3:24])=[O:22])=[C:15]([C:17](OC)=[O:18])[N:16]=1.Cl.O>O1CCCC1>[Br:11][C:12]1[N:13]([CH2:25][CH:26]=[C:27]([CH3:29])[CH3:28])[C:14]([C:21]([O:23][CH3:24])=[O:22])=[C:15]([CH:17]=[O:18])[N:16]=1
Reactant: COC(=O)c1nc(Br)n(CC=C(C)C)c1C(=O)OC
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1c(C=O)nc(Br)n1CC=C(C)C
Temperature: -65 °C

Procedure:
Under an argon atmosphere 35 ml (35 mmol) diisobutylaluminium hydride (1 mol/l in toluene) were added dropwise at −65° C. within 20 minutes to a solution of 9.00 g (12.18 mmol) dimethyl 2-bromo-1-(3-methyl-2-buten-1-yl)-1H-imidazole-4,5-dicarboxylate in 140 ml of tetrahydrofuran. After 1 hour at −65° C. another 5 ml (5 mmol) diisobutylaluminium hydride (1 mol/l in toluene) was added dropwise. The mixture was stirred for a further hour at −65° C. and then 20 ml of a 1:1 mixture of hydrochloric acid (1 mol/l) and tetrahydrofuran were added dropwise. After heating to ambient temperature approx. 100 ml of water was added, and the mixture was extracted three times with 70 ml of ethyl acetate. The extracts were dried over sodium sulphate, evaporated down, and the crude product thus obtained was purified by column chromatography (silica gel; eluant: cyclohexane/ethyl acetate 3:1->1:2).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[CH:23]=O)[CH:16]=[CH:15]1>O1CCCC1.C(OCC)(=O)C>[C:3](/[CH:5]=[CH:23]/[C:21]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:22]=1[NH:14][CH:15]=[CH:16]2)#[N:4]
Reactant: O=Cc1cccc2cc[nH]c12
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#C/C=C/c1cccc2cc[nH]c12
Reaction time: 0.25 h

Procedure:
Sodium hydride, 60% dispersion in mineral oil (0.10 g, 2.5 mmol) is added in portions over 10 minutes to a stirred solution of diethyl cyanomethylphosphonate (0.44 g, 2.5 mmol) in tetrahydrofuran (10 ml) cooled in ice. The mixture is stirred for 15 minutes then a solution of 7-indole carboxaldehyde (0.30 g, 2.1 mmol) in tetrahydrofuran (2 ml) is added dropwise. The mixture is stirred for 30 minutes, diluted with ethyl acetate, washed with water, dried and evaporated. The residue is chromatographed on silica in ethyl acetate-hexane (1:3) to give the product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[O:16])[CH:10]=2)=[C:4]([CH3:17])[CH:3]=1.[CH2:18]([O:20][CH2:21][CH2:22]Cl)[CH3:19].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.O>[CH2:18]([O:20][CH2:21][CH2:22][O:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[O:16])[CH:10]=2)=[C:4]([CH3:17])[CH:3]=1)[CH3:19]
Reactant: CCOCCCl
Reactant: Cc1cc(O)cc(C)c1-c1cccc(C=O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCCOc1cc(C)c(-c2cccc(C=O)c2)c(C)c1
Temperature: 80 °C
Reaction time: 18 h
Yield: 88.9 %

Procedure:
To a solution of 4′-hydroxy-2′,6′-dimethyl-3-biphenylcarbaldehyde (8.52 g, 37.7 mmol) and 2-chloroethyl ethyl ether (6.15 g, 56.6 mmol) in N,N-dimethylformamide (40 mL) were added potassium carbonate (6.25 g, 45.2 mmol) and potassium iodide (1.25 g, 7.54 mmol), and the mixture was stirred at 80° C. for 18 hr. Water was added to the reaction mixture, 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 (5%-25% ethyl acetate/hexane) to give the title compound (10.0 g, yield 89%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:3]=1[C:4]([NH:6][C:7]([CH3:21])([C:9]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[CH3:8])=[O:5].CC[N:29]([CH:33]([CH3:35])C)[CH:30](C)C.N1(N[S:41](Cl)(=[O:43])=[O:42])CCC1>CN(C=O)C>[Cl:1][C:2]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:3]=1[C:4]([NH:6][C:7]([CH3:21])([C:9]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:14][CH2:13][N:12]([S:41]([N:29]2[CH2:30][CH2:35][CH2:33]2)(=[O:43])=[O:42])[CH2:11][CH2:10]1)[CH3:8])=[O:5]
Reactant: O=S(=O)(Cl)NN1CCC1
Reactant: CC(C)(NC(=O)c1ccc(Cl)cc1Cl)C1(c2ccccn2)CCNCC1
Reactant: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(NC(=O)c1ccc(Cl)cc1Cl)C1(c2ccccn2)CCN(S(=O)(=O)N2CCC2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 2,4-Dichloro-N-{1-methyl-1-[4-pyridin-2-ylpiperidin-4-yl]ethyl}benzamide (V-1, 45 mg, 0.12 mmol) in DMF (1 mL) was cooled in an ice bath and treated with i-Pr2NEt (0.086 mL, 0.49 mmol) followed by azetidinylsulfamoyl chloride (literature reference J. Chem. Soc. Perkin 1 1994, p1595) (29 mg, 0.19 mmol). The mixture was allowed to warm to room temperature and stirred at room temperature for 12 h. The volatile components were removed in vacuo and the residue purified by preparative TLC eluting with 3% methanol-DCM to afford 2,4-dichloro-N-{1-methyl-1-[1-(azetidinesulfonyl)-4-pyridin-2-ylpiperidin-4-yl]ethyl}benzamide (V-2). 1H NMR (CDCl3, 500 MHz) δ 8.55 (d, J=3.4 Hz, 1H), 7.71 (t, J=7 Hz, 1H), 7.57 (d, J=8 Hz, 1H), 7.37 (m, 2H), 7.27 (m, 1H), 7.19 (m, 1H), 7.08 (s, 1H), 3.90 (t, J=7.5 Hz, 4H), 3.84 (d, J=6.5 Hz, 2H),), 3.46 (m, 2H), 3.30 (m, 2H), 2.31 (m, 2H), 2.22 (m, 2H), 1.94 (m, 2H); MS 483 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:8])[O:4][C:5](=[O:7])[CH:6]=1.[Br:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[F:18])[CH:13]=O.[C:19]1(=O)[CH2:23][CH2:22][C:21](=[O:24])[CH2:20]1>C(O)C>[Br:9][C:10]1[CH:11]=[C:12]([CH:13]2[C:6]3[C:5](=[O:7])[O:4][N:3]([CH3:8])[C:2]=3[NH:1][C:19]3[CH2:23][CH2:22][C:21](=[O:24])[C:20]2=3)[CH:15]=[CH:16][C:17]=1[F:18]
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: Cn1oc(=O)cc1N
Reactant: O=C1CCC(=O)C1
Solvent: CCO
Product: Cn1oc(=O)c2c1NC1=C(C(=O)CC1)C2c1ccc(F)c(Br)c1
Temperature: 25 °C
Yield: 18.5 %

Procedure:
The product from Example 45A (0.11 g, 1 mmol), 3-bromo-4-fluorobenzaldehyde (0.2 g, 1 mmol), and 1,3-cyclopentanedione (0.1 g, 1 mmol) in ethyl alcohol (2 mL) were heated at 80° C. for 2 days in a sealed tube. The reaction mixture was allowed to cool to ambient temperature and was evaporated under reduced pressure. The residue was chromatographed eluting with 19:0.5:0.5 ethylacetate:formic acid: water to provide the title compound (0.07 g). 1H NMR (300 MHz, DMSO-d6) δ 2.35 (t, 2H), 2.72 (m, 2H), 3.29 (s, 3H), 4.6 (s, 1H), 7.23 (d, 2H), 7.5 (d, 1H) 11.0 (s, 1H); MS (ESI) m/z 379 (M−H)−; Anal. Calcd for C16H12N3FBrO3: C, 50.68;H, 3.19; N, 7.39. Found: C, 50.34;H, 3.20; N, 7.34.
Reaction SMILES: [CH3:1][OH:2].C(N(CC)CC)C.[P:10](Cl)([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:11].Cl.C(N(CC)CC)C.ClCl>C1(C)C=CC=CC=1>[P:10]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])([O:2][CH3:1])=[O:11]
Reactant: CO
Reactant: CCCCCCCCCCCCOP(=O)(Cl)OCCCCCCCCCCCC
Agent: Cl
Agent: ClCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCOP(=O)(OC)OCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 5 g. (0.15 mole) of methanol and 12.12 g. (0.12 mole) of triethylamine in 200 ml. of toluene was stirred at ambient temperature (22° C.) and a total of 45.25 g. (0.1 mole) of dilauryl chlorophosphate (prepared as described in Preparation 1) was added dropwise over a period of 13 minutes. After the addition was complete, the reaction mixture was stirred for a further 1.5 hour at ambient temperature before being filtered to remove triethylamine hydrochloride (7.85 g.). The filtrate was heated to 95° C. for a few minutes before being cooled to 5° C. and filtered. The solid so isolated was a further 2.82 g. of triethylamine hydrochloride. The filtrate was evaporated to dryness and the residue was triturated with 150 ml. of ether. The insoluble material (triethylamine hydrochloride; 0.33 g.; total triethylamine hydrochloride=11 g.=80 percent theoretical) was removed by filtration and the filtrate was evaporated to dryness to yield 44 g. of methyl dilaurylphosphate which was found to contain 0.09 percent of hydrolyzable chlorine corresponding to the presence of 1.15 percent of starting material (dilauryl chlorophosphate).
Reaction SMILES: [N:1]1([C:5]2[N:10]=[C:9]([CH2:11][N:12]3[C@@H:16]([CH3:17])[C@@H:15]([C:18]4[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=4)[O:14][C:13]3=[O:32])[C:8]([C:33]3[CH:38]=[C:37](B4OCC(C)(C)CO4)[CH:36]=[CH:35][C:34]=3[O:47][CH3:48])=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1.Br[C:50]1[S:54][C:53]([C:55]([O:57][CH3:58])=[O:56])=[CH:52][C:51]=1[CH3:59].N#N.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[N:1]1([C:5]2[N:10]=[C:9]([CH2:11][N:12]3[C@@H:16]([CH3:17])[C@@H:15]([C:18]4[CH:19]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:21]=[C:22]([C:24]([F:26])([F:25])[F:27])[CH:23]=4)[O:14][C:13]3=[O:32])[C:8]([C:33]3[CH:38]=[C:37]([C:50]4[S:54][C:53]([C:55]([O:57][CH3:58])=[O:56])=[CH:52][C:51]=4[CH3:59])[CH:36]=[CH:35][C:34]=3[O:47][CH3:48])=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(B2OCC(C)(C)CO2)cc1-c1ccc(N2CCC2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reactant: COC(=O)c1cc(C)c(Br)s1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(C)c(-c2ccc(OC)c(-c3ccc(N4CCC4)nc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (4S,5R)-3-({6-azetidin-1-yl-3-[5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-methoxyphenyl]pyridin-2-yl}methyl)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (27 mg, 0.040 mmol) and methyl 5-bromo-4-methyl-2-thiophene carboxylate (18.74 mg, 0.080 mmol) in THF (0.5 mL) was degassed with N2 at 25° C. 1N K2CO3 (0.5 mL) was added followed by 1,1-bis(di-tert-butylphosphino) ferrocene palladium dichloride (2.60 mg, 3.99 mmol) and the reaction was stirred vigorously at 25° C. under N2 overnight. The reaction was diluted with water and extracted with EtOAc (3×). The combined extracts were dried (Na2SO4) and concentrated in vacuo to afford the crude product. This was purified by preparative TLC (20×20, 1000 μm, hexanes/EtOAc (70/30)) to give methyl 5-{3-[6-azetidin-1-yl-2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)pyridin-3-yl]-4-methoxyphenyl}-4-methylthiophene-2-carboxylate. LCMS calc.=719.2. found=720.2 (M+H)+. 1H NMR (500 MHz, CDCl3): δ 7.86 (s, 1H); 7.73 (s, br, 2H); 7.62 (s, 1H); 7.47 (d, J=8.6 Hz, 1H); 7.35 (d, J=8.6 Hz, 1H); 7.33-7.23 (m, 1H); 7.03 (d, J=8.6 Hz, 1H); 6.31 (d, J=8.3 Hz, 1H); 5.74-5.31 (m, 1H); 4.87 (d, J=16.2 Hz, 1H); 4.24 (s, br, 1H); 4.23-3.97 (m, 5H); 3.88 (s, 3H); 3.87 (s, 3H); 2.47-2.41 (m, 2H); 2.33 (s, 3H); 0.75-0.53 (m, 3H).