Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17][CH3:18].ClC1C=CC=C(C(OO)=[O:27])C=1>ClCCl>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([CH3:18])=[O:27]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccccc1-c1nc2ccccc2n1C
Solvent: ClCCl
Product: Cn1c(-c2ccccc2S(C)=O)nc2ccccc21
Temperature: 25 °C

Procedure:
The product of step (b) above (2 g) was dissolved in dichloromethane (50 mls) and cooled to -10° with stirring. 85% m-chloroperbenzoic acid (1.6 g) was added portionwise. The reaction mixture was slowly warmed to room temperature and after 3 hours the reaction was complete. The reaction mixture was washed with aqueous metabisulphite solution, then bicarbonate solution and finally brine, dried over magnesium sulphate and evaporated to dryness in vacuo, then the residue was purified by flash chromatography (SiO2 /ethyl acetate 3:2 CH2Cl2) to afford the sub-title compound as a yellow crystalline solid, mp 157°-159°.
Reaction SMILES: C(O[C:4]([C:6]1[CH:10]=[C:9]([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[O:8][N:7]=1)=[O:5])C.[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>>[N:20]1([C:4]([C:6]2[CH:10]=[C:9]([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[O:8][N:7]=2)=[O:5])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: C1CCNC1
Reactant: CCOC(=O)c1cc(CNC(=O)OC(C)(C)C)on1
Product: CC(C)(C)OC(=O)NCc1cc(C(=O)N2CCCC2)no1
Temperature: 85 °C
Yield: 79 %

Procedure:
3-Ethoxycarbonyl-5-[N-(tert-butyloxycarbonyl)aminomethyl]isoxazole (Method 73; 500 mg, 1.85 mmol) was dissolved in pyrrolidine (4 ml) and the mixture heated for 3 hours at 85° C. The volatiles were removed by evaporation and the residue was triturated with diethyl ether to give the title compound (432 mg, 79%) as a white solid. NMR (DMSO): 1.38 (s, 9H), 1.85 (m, 4H), 3.50 (t, 2H), 3.62 (t, 2H), 4.29 (d, 2H), 6.47 (1H), 7.53 (s, 1H); m/z 240 (M-C4H8)+.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:33][CH2:34][OH:35])[C:7]2[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[N:10]=[C:9]([N:17]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:8]=2[N:32]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>ClCCl>[CH3:43][S:44]([O:35][CH2:34][CH2:33][N:6]1[C:7]2[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[N:10]=[C:9]([N:17]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:8]=2[N:32]=[C:5]1[CH2:1][CH2:2][CH2:3][CH3:4])(=[O:46])=[O:45]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCc1nc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc3c(c2n1CCO)CCCC3
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCc1nc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc3c(c2n1CCOS(C)(=O)=O)CCCC3
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 95.6 %

Procedure:
A round bottom flask was charged with a magnetic stir bar, di(tert-butyl) 2-butyl-1-(2-hydroxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-ylimidodicarbonate (0.55 g, 1.13 mmol) and anhydrous dichloromethane (11 mL) under a nitrogen atmosphere. The resulting homogeneous solution was cooled to −10° C. in a methanol/ice bath. To the cooled solution was added triethylamine (0.23 g, 2.26 mmol) and methanesulfonyl chloride (0.19 g, 1.70 mmol). The reaction was judged to be complete after stirring at −10° C. for 15 minutes and was then partitioned between ethyl acetate and saturated aqueous ammonium chloride. The layers were separated. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford 2-{4-[bis(tert-butoxycarbonyl)amino]-2-butyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl}ethyl methanesulfonate (0.61 g, 1.08 mmol) as a gummy yellow solid. The material was used without further purification. MS (CI) for C27H42N4O7S m/z 567 (MH+), 467, 367, 271.
Reaction SMILES: [O:1]1[C:13]2[C:4](=[CH:5][C:6]3[NH:10][C:9]([SH:11])=[N:8][C:7]=3[CH:12]=2)[O:3][CH2:2]1.Cl.Cl[CH2:16][C:17]1[C:22]([CH3:23])=[C:21]([O:24][CH3:25])[C:20]([CH3:26])=[CH:19][N:18]=1.[OH-].[Na+]>O>[CH3:25][O:24][C:21]1[C:20]([CH3:26])=[CH:19][N:18]=[C:17]([CH2:16][S:11][C:9]2[NH:10][C:6]3[CH:5]=[C:4]4[O:3][CH2:2][O:1][C:13]4=[CH:12][C:7]=3[N:8]=2)[C:22]=1[CH3:23]
Reactant: COc1c(C)cnc(CCl)c1C
Reactant: Sc1nc2cc3c(cc2[nH]1)OCO3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1c(C)cnc(CSc2nc3cc4c(cc3[nH]2)OCO4)c1C

Procedure:
14.8 g of 5H-1,3-dioxolo[4,5-f]benzimidazole-6-thiol were suspended in 300 ml of alcohol and the suspension was treated while cooling with ice with 17.0 g of 2-chloromethyl-4-methoxy-3,5-dimethylpyridine hydrochloride. Thereafter, a solution of 6.0 g of sodium hydroxide in 150 ml of water was added dropwise thereto, the mixture was left to boil at reflux overnight and subsequently evaporated to dryness in vacuo. The residue was dissolved in 1000 ml of methylene chloride. The solution was washed firstly with 500 ml of 1.5N sodium hydroxide solution and then with 3×500 ml of water, dried over sodium sulfate and evaporated in vacuo. The product was purified on 300 g of silica gel using ethyl acetate/methylene chloride (1:1) as the elution agent. Crystallization from methylene chloride/petroleum ether gave 6-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]-5H-1,3-dioxolo[4,5-f]benzimidazole of melting point 178°-179°.
Reaction SMILES: [Li+].[BH4-].[Br:3][C:4]1[CH:5]=[C:6]([NH:19][CH2:20][C:21]2[C:26]([CH3:27])=[CH:25][C:24]([F:28])=[CH:23][C:22]=2[CH3:29])[C:7]2[N:8]([C:10]([C:14](OCC)=[O:15])=[C:11]([CH3:13])[N:12]=2)[CH:9]=1>C1COCC1>[Br:3][C:4]1[CH:5]=[C:6]([NH:19][CH2:20][C:21]2[C:26]([CH3:27])=[CH:25][C:24]([F:28])=[CH:23][C:22]=2[CH3:29])[C:7]2[N:8]([C:10]([CH2:14][OH:15])=[C:11]([CH3:13])[N:12]=2)[CH:9]=1
Reactant: CCOC(=O)c1c(C)nc2c(NCc3c(C)cc(F)cc3C)cc(Br)cn12
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(F)cc(C)c1CNc1cc(Br)cn2c(CO)c(C)nc12
Yield: 44.3 %

Procedure:
LiBH4 (70 mg) was added in portions and during 4 h to a refluxed solution of 6-bromo-3-carboethoxy-8-(2,6-dimethyl-4-fluorobenzylamino)-2-methylimidazo[1,2-a]pyridine (100 mg, 0.23 mmol) in THF. The reaction mixture was quenched by addition of diluted HCl and methylene chloride was added. The organic layer was separated, dried and evaporated in vacuo. The residue was purified by column chromatography on silica gel, using methylene chloride:ethyl acetate (100:10) as eluent to give 40 mg (44%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([NH2:13])[S:11][CH:12]=1.[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[C:16]=1[S:23](Cl)(=[O:25])=[O:24]>>[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[C:16]=1[S:23]([NH:13][C:10]1[S:11][CH:12]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[N:9]=1)(=[O:25])=[O:24]
Reactant: Nc1nc(-c2ccccc2Cl)cs1
Reactant: O=S(=O)(Cl)c1c(Cl)cc(Cl)cc1Cl
Product: O=S(=O)(Nc1nc(-c2ccccc2Cl)cs1)c1c(Cl)cc(Cl)cc1Cl

Procedure:
The title compound was prepared from 4-(2-chlorophenyl)-1,3-thiazol-2-amine and 2,4,6-trichlorobenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (38.7 mg) with purity >90%. MS (pos) m/z 453.0, 455.0, 457.0.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH3:13])[C:6]=1[CH3:14])=[O:4].[Br:15]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH3:13])[C:6]=1[CH2:14][Br:15])=[O:4]
Reactant: COC(=O)c1cc(Br)c(=O)n(C)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(Br)c(=O)n(C)c1CBr
Yield: 51.5 %

Procedure:
A mixture of 5-bromo-1,2-dimethyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid methyl ester (540 mg, 2.08 mmol), N-bromosuccinimide (388 mg, 2.18 mmol), and benzoyl peroxide (50 mg, 0.208 mmol) in CCl4 (20 mL) was refluxed for 16 h. The solvent was evaporated in vacuo, and the residue was chromatographed (0-50% EtOAc/hexanes) to give 363 mg of the title compound. MS: (+) m/z 340.02 (M+1).
Reaction SMILES: Br[C:2]1[C:3]([NH:11][C:12](=[O:21])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[N:7][C:6]=12.[CH3:22][C:23]([CH3:30])([CH3:29])[CH:24]=[CH:25]B(O)O>>[CH3:22][C:23]([CH3:30])([CH3:29])/[CH:24]=[CH:25]/[C:2]1[C:3]([NH:11][C:12](=[O:21])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[N:7][C:6]=12
Reactant: O=C(Cc1ccc(F)cc1)Nc1nn2cccnc2c1Br
Reactant: CC(C)(C)C=CB(O)O
Product: CC(C)(C)/C=C/c1c(NC(=O)Cc2ccc(F)cc2)nn2cccnc12

Procedure:
The product from Example 140A and 3,3-dimethyl-1-butenylboronic acid were processed using the method analogous to that described in Example 110C to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.32-10.43 (bs, 1H), 8.99 (dd, J=7.0, 1.7 Hz, 1H), 8.56 (dd, J=4.1, 1.7 Hz, 1H), 7.37-7.43 (m, 2H), 7.13-7.21 (m, 2H), 7.04 (dd, J=7.0, 4.1 Hz, 1H), 6.63 (d, J=16.3 Hz, 1H), 6.08 (d, J=16.5 Hz, 1H), 3.70 (s, 2H), 1.01 (s, 9H); MS (APCI) m/z 353 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2([CH3:28])[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH2:11][CH2:10]1.[C:29](N1C=CN=C1)(N1C=CN=C1)=[O:30]>C(#N)C>[O:30]=[C:29]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]3([CH3:28])[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]3)[CH2:11][CH2:10]2)[C@H:3]2[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]2[NH:1]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(N2CCC(N[C@@H]3CCCC[C@H]3N)CC2)CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(C)(N2CCC(N3C(=O)N[C@H]4CCCC[C@@H]43)CC2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 30 %

Procedure:
A solution of tert-butyl 4-[4-[[(1R,2R)-2-aminocyclohexyl]amino]-1-piperidyl]-4-methyl-piperidine-1-carboxylate in acetonitrile (20 mL) was added with 1,1′-carbonyldiimidazole (1.30 g, 8.0 mmol) and the reaction mixture was stirred at room temperature for 12 h. The solvent was removed in vacuo and the residue was taken up in water (20 mL) and dichloromethane (80 mL). The phases were separated and the aqueous phase was extracted with dichloromethane (2×50 mL). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product, which was purified with preparative LC/MS (high pH) to give the title compound as white solid (849 mg, 30% over two steps). 1H NMR (400 MHz, METHANOL-D4) δ ppm 0.95 (s, 3H), 1.31-1.40 (m, 4H), 1.42 (s, 9H), 1.44-1.48 (m, 2H), 1.52-1.63 (m, 1H), 1.64-1.89 (m, 8H), 1.93-1.99 (m, 1H), 2.08-2.21 (m, 2H), 2.25-2.32 (m, 1H), 2.89-3.10 (m, 4H), 3.28-3.36 (m, 1H), 3.42-3.53 (m, 2H), 3.54-3.65 (m, 1H). MS (M+1): 421.3.
Reaction SMILES: [Cl-].[NH4+:2].C[Al](C)C.[CH2:7]([N:14]1[C:26]2[CH2:25][CH2:24][CH2:23][CH:22]([C:27](OCC)=[O:28])[C:21]=2[C:20]2[C:15]1=[C:16]([CH3:34])[CH:17]=[CH:18][C:19]=2[O:32][CH3:33])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1(C)C=CC=CC=1.ClCCl>[CH2:7]([N:14]1[C:26]2[CH2:25][CH2:24][CH2:23][CH:22]([C:27]([NH2:2])=[O:28])[C:21]=2[C:20]2[C:15]1=[C:16]([CH3:34])[CH:17]=[CH:18][C:19]=2[O:32][CH3:33])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)C1CCCc2c1c1c(OC)ccc(C)c1n2Cc1ccccc1
Reactant: [NH4+]
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1ccc(C)c2c1c1c(n2Cc2ccccc2)CCCC1C(N)=O
Temperature: 50 °C
Yield: 98.5 %

Procedure:
A slurry of 0.38 g of ammonium chloride in 15 ml of dry toluene was cooled in an ice bath and treated with 3.5 ml of a 2.0 M solution of trimethylaluminum in toluene. This mixture was stirred for 1 hour at room temperature, whereupon 0.762 g (2.02 mmol) of ethyl 9-benzyl-5-methoxy-8-methyl-1,2,3,4-tetrahydrocarbazole-4-carboxylate in 10 ml of toluene and 1 ml of dichloromethane was added. The mixture was heated to 50° C. overnight, cooled and quenched with 20 ml of aqueous 5% HCl solution. Ethyl acetate extracts (3×100 ml) were washed with water and then with brine, dried over magnesium sulfate and concentrated to afford 0.693 g (98%) of the subtitle compound. ESIMS m/e 349 (M++1) NMR (300 MHz, CDCl3): δ7.25 (m, 3H); 6.83 (d, J=7.2, 2H); 6.74 (d, J=7.8, 1H); 6.40 (d, J=7.8, 1H); 5.93 (br, 1H); 5.54 and 5.45 (ABq, J=17.7, 2H); 5.42 (br, 1H); 4.14 (br, 1H); 3.87 (s, 3H); 2.65 (dt, J=16.4, 4.1, 1H); 2.55-2.36 (m,2H); 2.45 (s, 3H); 1.97-1.86 (m, 3H).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:40]=[C:41]([O:54][CH3:55])[C:42]=1[CH2:43][C@H:44]1[C@:46]([CH3:53])([CH2:47][CH2:48][CH:49]=[C:50]([CH3:52])[CH3:51])[O:45]1)[O:29][Si](C(C)C)(C(C)C)C(C)C.CCCCCC>CCOC(C)=O>[CH3:55][O:54][C:41]1[CH:40]=[C:28]([OH:29])[CH:27]=[C:26]([O:25][CH3:24])[C:42]=1[CH2:43][C@H:44]1[C@:46]([CH3:53])([CH2:47][CH2:48][CH:49]=[C:50]([CH3:52])[CH3:51])[O:45]1
Reactant: COc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(OC)c1C[C@@H]1O[C@@]1(C)CCC=C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(O)cc(OC)c1C[C@@H]1O[C@@]1(C)CCC=C(C)C
Reaction time: 0.5 h
Yield: 83.7 %

Procedure:
Tetrabutylammonium fluoride in THF (1 M, 9.0 mL, 9.01 mmol, 1.05 equiv.) was added to a THF (30 mL) solution of 5 (3.97 g, 8.58 mmol, 1 equiv.) in a 100-mL pear-shaped flask. After stirring for 30 min, the reaction was quenched with saturated aqueous NH4Cl and extracted once with hexane and twice with EtOAc. The organic extracts were combined, washed with brine, Na2SO4, filtered, and concentrated in vacuo to a slight yellow oil. Flash column chromatography (400 mL SiO2, 7:3 to 1:1 hexane:EtOAc) afforded 2.20 g (7.18 mmol, 84% yield) of 6 as a clear, colorless oil. TLC Rf 0.5 (1:1 hexane:EtOAc). 1H NMR (500 MHz; CDCl3): δ 6.06 (s, 2H), 5.11 (s, 1H), 4.99 (t, J=7.1 Hz, 1H), 3.76 (s, 6H), 2.97 (dd, J=13.5, 4.6 Hz, 1H), 2.91 (dd, J=7.3, 4.6 Hz, 1H), 2.69 (dd, J=13.5, 7.3 Hz, 1H), 2.07-1.95 (m, 2H), 1.63 (ddd, J=13.9, 9.1, 5.2 Hz, 1H), 1.59 (s, 3H), 1.54 (s, 3H), 1.38 (s, 3H), 1.37-1.33 (m, 1H). 13C NMR (125 MHz; CDCl3): δ 159.3, 156.4, 131.9, 123.8, 106.1, 92.1, 64.1, 62.6, 55.7, 39.1, 25.8, 24.1, 22.3, 17.7, 16.9. IR (NaCl, thin film, cm−1) 3368 (br), 2936, 2840, 1618, 1603, 1475, 1431, 1206, 1134, 999, 816.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10]CC2C=CC=CC=2)=[CH:6][C:5]=1[CH2:18][C:19]#[N:20])([O-])=O.C1CCCCC=1>[Pd].C(O)C>[C:19]([CH2:18][C:5]1[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:4]=1[NH2:1])#[N:20]
Reactant: N#CCc1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: N#CCc1cc(O)ccc1N

Procedure:
A suspension of 5.4 g of 2-nitro 5-benzyloxyphenylacetonitrile, 5.4 ml of cyclohexene, 22 ml of ethanol and 3 g of 10% palladium on activated charcoal was refluxed for five hours. The suspension was then hot filtered and the filtrate evaporated. The residue was recrystallised from ethanol to produce dark beige crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]([C@@H:11]1[CH2:16][CH2:15][CH:14]=[CH:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C@@H]1(C(O)=[O:24])CCC=CC1>>[CH2:1]([O:8][C:9]([C@@H:11]1[CH2:16][CH2:15][C@@H:14]2[C@@H:13]([O:24]2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)[C@H]1CC=CCC1
Reactant: O=C(O)[C@H]1CC=CCC1
Product: O=C(OCc1ccccc1)[C@@H]1CC[C@H]2O[C@H]2C1

Procedure:
In a manner similar to that employed in Referential Example 99, (1R)-3-cyclohexene-1-carboxylic acid benzyl ester was prepared from (1R)-3-cyclohexene-1-carboxylic acid (J. Am. Chem. Soc, vol. 100, p. 5199 (1978)).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=[O:10])[CH2:5][C:6]([O:8][CH3:9])=[O:7].C1(C)C=CC(S([N:20]=[N+:21]=[N-])(=O)=O)=CC=1.C(NCC)C>CCOCC>[N+:20](=[C:5]([C:4](=[O:10])[CH2:3][O:2][CH3:1])[C:6]([O:8][CH3:9])=[O:7])=[N-:21]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: COCC(=O)CC(=O)OC
Solvent: CCOCC
Solvent: CCNCC
Product: COCC(=O)C(=[N+]=[N-])C(=O)OC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 90.1 %

Procedure:
Methyl 4-methoxy-3-oxobutanoate (4.28 g, 0.029 mol) was dissolved in ether (20 mL). The solution was cooled in an ice bath. To the solution was added p-toluenesulfonyl azide (5.78 g, 0.029 mol) followed by N-ethylethanamine (2.0 mL, 0.019 mol). The solution was stirred at 0° C. for 15 minutes, then at rt for 30 minutes. Upon evaporation, the tosyl amide bi-product solidified. This was filtered off and the filtrate was purified by flash chromatography to give the desired product (4.5 g, 89%) as a light oil. 1H NMR (400 MHz, CDCl3): δ 4.55 (s, 2H), 3.83 (s, 3H), 3.45 (s, 3H). MF═C6H8N2O4. LCMS calculated for C6H9N2O4 (M+H)+: m/z=173.0.
Reaction SMILES: [CH3:1][C:2]([SH:8])([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].FC(F)(F)C(O)=O.[CH3:16][O:17][C:18]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][CH3:29])[C:19]=1CO>C(Cl)Cl>[CH3:1][C:2]([S:8][C:19]1[C:22]([O:28][CH3:29])=[CH:23][C:24]([O:26][CH3:27])=[CH:25][C:18]=1[O:17][CH3:16])([CH3:7])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: COc1cc(OC)c(CO)c(OC)c1
Reactant: CC(C)(S)CC(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OC)c(SC(C)(C)CC(=O)O)c(OC)c1
Temperature: 5 °C
Reaction time: 0.08 h
Yield: 70 %

Procedure:
To a solution of 3-methyl-3-sulfanylbutanoic acid (Sweetman et al, J. Med Chem.,14:868 (1971), the disclosure of which is incorporated herein by reference in its entirety) (4.6 g, 34 mmol) in methylene chloride (250 mL) under nitrogen and cooled over ice/salt to 5° C. (internal temperature) was added trifluoroacetic acid (82 g, 0.72 mol). No significant temperature rise was noted during the addition. To this was then added dropwise a solution of 2,4,6-trimethoxybenzyl alcohol (Munson et al., J. Org. Chem., 57, 3013 (1992), the disclosure of which is incorporated herein by reference in its entirety) (6.45 g, 32 mmol) in methylene chloride (150 mL) such that the reaction temperature does not rise above 5° C. After the addition was complete, the mixture was stirred for an additional 5 minutes at 5° C. and the volatiles were evaporated in vacuo (toluene or ethyl acetate can be used to assist in the removal of volatile material). The residue was partitioned between diethyl ether and water and the organic phase dried over anhydrous sodium sulfate, filtered and the volatile material evaporated in vacuo. The residue was treated with activated charcoal and recrystalized from diethyl ether/hexane. The product was isolated as a white solid in 70% yield (7 g). mp 103-105° C.; 1H NMR(CDCl3): δ6.12 (s, 2H), 3.80-3.85 (m, 11H), 2.74 (s, 2H), 1.47 (s, 6H). 13C NMR (CDCl3): δ173.9, 160.6, 158.6, 105.6, 90.5, 55.7, 55.3, 45.9, 43.6, 28.4, 21.0.
Reaction SMILES: [N+](C1C=C(S([O:13][CH2:14][C@:15]2([CH3:18])[CH2:17][O:16]2)(=O)=O)C=CC=1)([O-])=O.C([O-])([O-])=O.[K+].[K+].[C:25]([C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1)#[N:26]>CC#N>[CH3:18][C@@:15]1([CH2:14][O:13][C:30]2[CH:31]=[CH:32][C:27]([C:25]#[N:26])=[CH:28][CH:29]=2)[CH2:17][O:16]1
Reactant: N#Cc1ccc(O)cc1
Reactant: C[C@@]1(COS(=O)(=O)c2cccc([N+](=O)[O-])c2)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@]1(COc2ccc(C#N)cc2)CO1

Procedure:
A suspension of [(2S)-2-methyloxiran-2-yl]methyl 3-nitro-1-benzenesulfonate (37.7 g; 138 mmol; from step (a) above), K2CO3 (28 g) and p-cyanophenol (23.8 g; 200 mmol) in MeCN (300 mL) was refluxed for 20 h. The reaction mixture was ffiltered and the filtrate concentrated under reduced pressure, dissolved in ether and washed with 2M NaOH and then brine. The organic layer was concentrated and subjected to column chromatography (petroleum ether:EtOAc; 3:1) to give the sub-title compound.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:16][CH2:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1.Br[C:28]1[CH:29]=[C:30]([CH:34]=[C:35]([F:37])[CH:36]=1)[C:31]([OH:33])=[O:32].C(=O)([O-])[O-].[Cs+].[Cs+]>[Pd].ClC1C=C[C-](P(C2C=CC=CC=2)C2C=CC=CC=2)C=1Cl.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:16][CH2:17][C:18]1[CH:19]=[C:20]([C:28]2[CH:36]=[C:35]([F:37])[CH:34]=[C:30]([C:31]([OH:33])=[O:32])[CH:29]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: O=C(O)c1cc(F)cc(Br)c1
Reactant: CC(C)(C)Cn1nnc2c(Br)c(OCc3cccc(B(O)O)c3)ccc21
Agent: [Fe+2]
Agent: [Pd]
Agent: Clc1cc[c-](P(c2ccccc2)c2ccccc2)c1Cl
Product: CC(C)(C)Cn1nnc2c(Br)c(OCc3cccc(-c4cc(F)cc(C(=O)O)c4)c3)ccc21

Procedure:
[3-({[4-Bromo-1-(2,2-dimethylpropyl)-1H-1,2,3-benzotriazol-5-yl]oxy}methyl)phenyl]boronic acid (3-1) (400 mg, 0.957 mmol, 1.0 equiv.), 3-bromo-5-fluorobenzoic acid (12) (800 mg, 3.65 mmol, 3.8 equiv.) and dichloro[1,1′-bis (diphenylphosphino) ferrocene] palladium II dichloromethane adduct (78 mg, 0.096 mmol, 0.1 equiv.) were dissolved in anhydrous degassed 1,4-dioxane (8 mL), then treated with a 1 M aqueous solution of cesium carbonate (5.2 mL, 5.3 mmol, 5.5 equiv.). The reaction mixture was irradiated in microwavereactor at 150° C. for 10 minutes. The mixture was concentrated in vacuo and purified by reverse phase HPLC (H2O/CH3CN gradient w/0.1% TFA present) to afford Example 3-2. 1H NMR δ (CDCl3): 8.15 (s, 1H), 7.77 (s, 2H), 7.58-7.52 (m, 4H), 7.41 (d, 1H, J=8.5 Hz), 7.29 (d, 1H, J=9.0 Hz), 5.32 (s, 2H), 4.38 (s, 2H), 1.04 (s, 9H) ppm. LRMS m/z (M+H) 512.0 and 514.0 (intensity ratio ˜1:1) found, 512.1 and 514.1 required.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:11][N:12]([CH:21]=[O:22])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:23][C:24]1[NH:25][C:26]([NH:33][CH:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[C:27]([F:32])[C:28](=[N:30][NH2:31])[N:29]=1.CN1CCOCC1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[Cl:23][C:24]1[N:29]=[C:28]([NH:30][NH:31][C:8](=[O:10])[C@H:7]([CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH2:11][N:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[O:22])[C:27]([F:32])=[C:26]([NH:33][CH:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[N:25]=1
Reactant: NN=c1nc(Cl)[nH]c(NC2CCOCC2)c1F
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OCc1ccccc1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=CN(C[C@@H](CC1CCCC1)C(=O)NNc1nc(Cl)nc(NC2CCOCC2)c1F)OCc1ccccc1
Reaction time: 8 h
Yield: 81.2 %

Procedure:
(2R)-3-Cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoic acid (0.220 g, 0.72 mmol), 2-chloro-5-fluoro-6-(tetrahydro-2H-pyran-4-ylamino)-4(1H)-pyrimidinone hydrazone (0.199 g), NMM (0.42 mL, 3.80 mmol), HOAt (0.103 g, 0.76 mmol), EDC (0.146 g, 0.76 mmol) were dissolved in DMF (5 mL). Reaction left to stir overnight. Added ether, washed with water, back extracted aqueous layers with ether, dried (Na2SO4) and concentrated in vacuo to provide [(2R)-3-{2-[2-chloro-5-fluoro-6-(tetrahydro-2H-pyran-4-ylamino)-4-pyrimidinyl]hydrazino}-2-(cyclopentylmethyl)-3-oxopropyl][(phenylmethyl)oxy]formamide as a dark brown solid (0.321 g). LCMS: (M+H)+=549.2.