Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH2:5][OH:6])[CH2:3][OH:4].[Na].Br[CH2:16][C:17]1[CH:18]=[C:19]([CH:32]=[C:33]([N:35]([CH3:40])[S:36]([CH3:39])(=[O:38])=[O:37])[CH:34]=1)[C:20]([NH:22][C@@H:23]([C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)[CH3:24])=[O:21]>CN(C=O)C.C1COCC1>[NH2:1][C:2]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH2:3][OH:4])[CH2:5][O:6][CH2:16][C:17]1[CH:18]=[C:19]([CH:32]=[C:33]([N:35]([CH3:40])[S:36]([CH3:39])(=[O:38])=[O:37])[CH:34]=1)[C:20]([NH:22][C@@H:23]([C:25]1[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=1)[CH3:24])=[O:21]
Reactant: C[C@@H](NC(=O)c1cc(CBr)cc(N(C)S(C)(=O)=O)c1)c1ccc(F)cc1
Reactant: NC(CO)(CO)Cc1ccccc1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)c1cc(COCC(N)(CO)Cc2ccccc2)cc(N(C)S(C)(=O)=O)c1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of intermediate I 2-amino-2-benzylpropane-1,3-diol (0.09 g, 0.50 mmol) in 2 mL DMF cooled to 0° C. was added sodium hexamethyldisylazide (0.5 mL, 0.50 mmol, 1 M in THF). The reaction mixture was stirred at 0° C. for 5 min and intermediate A 3-(bromomethyl)-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[methyl(methylsulfonyl)amino]benzamide (0.1 g, 0.23 mmol) in 1 mL DMF was added dropwise. The reaction mixture was stirred at 0° C. for 0.5 h, quenched with water, extracted with EtOAc, washed with aq LiCl (3×), dried over sodium sulfate, concentrated in vacuo, and purified by flash chromatography (40 g silica, 0→8% (10% NH4OH in MeOH)/CH2Cl2) to afford 3-[(2-amino-2-benzyl-3-hydroxypropoxy)methyl]-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[methyl(methylsulfonyl)amino]benzamide. 1H NMR (400 MHz, d4-MeOH) δ 7.80 (s, 2H), 7.64 (s, 1H), 7.44-7.40 (m, 2H), 7.26-7.20 (m, 5H), 7.07-7.02 (m, 2H), 5.24 (q, J=7.0 Hz, 1H), 4.61 (s, 2H), 3.48 (A of AB, d, J=10.4 Hz, 1H), 3.43 (B of AB, d, J=10.4 Hz, 1H), 3.35 (s, 3H), 2.91 (s, 3H), 2.72 (A of AB, d, J=13.9 Hz, 1H), 2.66 ((B of AB, d, J=13.9 Hz, 1H), 1.57 (d, J=7.0 Hz, 3H). HRMS calculated for C28H34FN3O5S+H: 544.2276, found: 544.2275
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].C([Li])(C)(C)C.[CH3:14][O:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1Br.[Cl-].C1(C)C=CC=CC=1[Zn+]>O1CCCC1.CCCCC.Cl[Ni](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:14][O:15][C:16]([C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH3:8])=[CH:19][CH:18]=1)=[O:24]
Reactant: COC(=O)c1ccccc1Br
Reactant: Cc1ccccc1Br
Agent: Cl[Ni](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cc1ccccc1[Zn+]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCCCC
Product: COC(=O)c1ccc(-c2ccccc2C)cc1
Temperature: -78 °C
Yield: 86.5 %

Procedure:
A 2 L three-necked 24/40 round-bottom flask equipped with a mechanical stirrer, a 500 mL constant pressure addition funnel with a nitrogen inlet at the top, and a septum was flame dried, cooled and then charged with a solution of 70.00 g (0.409 mol) of o-bromotoluene in 350 mL of anhydrous tetrahydrofuran under a nitrogen atmosphere. The solution was stirred and cooled to -78° C. and 481 mL (0.818 mol) of a 1.7M solution of t-butyllithium in pentane was added via the addition funnel over 45 minutes. When the addition was complete, the cooling bath was removed and the reaction mixture was stirred for 45 minutes and allowed to warm to room temperature. The dropping funnel was next charged with 409 mL (0.409 mol) of a 1.0M solution of zinc chloride in diethylether which was added to the reaction mixture over a 20 minute period. A separate 2 L three-necked 24/40 round-bottom flask equipped with a mechanical stirrer, a nitrogen inlet and a septum, was flame dried, cooled and then charged with 8.93 g (13.7 mmol) of bis(triphenylphosphine)nickel(II) chloride, 58.71 g (0.273 mol) of methyl-2-bromobenzoate and 450 mL of anhydrous tetrahydrofuran under a nitrogen atmosphere. The suspension of the tolylzinc chloride was then transferred to the second flask via a wide diameter cannula. The reaction mixture was stirred an additional 45 minutes at room temperature, then most of the tetrahydrofuran was removed on a rotary evaporator. The resulting oil was partitioned between ethyl acetate (500 mL) and water (300 mL). The organic layer was washed successively with water, 5% hydrochloric acid, water, and brine, then dried (MgSO4), filtered and evaporated. The residual oil was purified on a Waters Prep 500 HPLC (2 silica packs) eluted with 1.5% ethyl acetate-hexane in eleven separate runs (mixed fractions recycled, 10 g per injection). The purified fractions were evaporated and freed of residual solvent in vacuo to afford 53.42 g (74%) of a colorless oil which had: NMR (CDCl3) δ2.25 (s, 3H), 3.93 (s, 3H), 7.19-7.28 (m, 4H), 7.39 (d, J=12 Hz, 2H), 8.08 (d, J=12 Hz, 2H); MS (FAB) m/e (MH+).
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([Br:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[N:30]1([CH2:35][CH2:36][CH2:37][CH2:38][NH2:39])[CH2:34][CH2:33][CH2:32][CH2:31]1>>[Br:24][C:20]1[CH:19]=[C:18]([F:25])[C:17]([CH2:16][O:15][C:12]2[C:11]([C:26]([NH2:27])=[O:28])=[C:10]([NH:9][C:8]([NH:39][CH2:38][CH2:37][CH2:36][CH2:35][N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[O:29])[S:14][N:13]=2)=[C:22]([F:23])[CH:21]=1
Reactant: NC(=O)c1c(OCc2c(F)cc(Br)cc2F)nsc1NC(=O)Oc1ccccc1
Reactant: NCCCCN1CCCC1
Product: NC(=O)c1c(OCc2c(F)cc(Br)cc2F)nsc1NC(=O)NCCCCN1CCCC1

Procedure:
The title compound was prepared from [3-(4-bromo-2,6-difluoro-benzyloxy)4-carbamoyl-isothiazol-5-yl]-carbamic acid phenyl ester and 4-pyrrolidin-1-yl-butylamine by the procedure analogous to Example 1. MS (APCI, m/z): 532 and 534 [M+H]+.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[CH:11][C:12]([O:16][CH3:17])=[C:13]([CH:15]=2)[NH2:14])[CH2:3]1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>N1C=CC=CC=1>[CH3:8][C@H:6]1[NH:7][C@@H:2]([CH3:1])[CH2:3][N:4]([C:9]2[CH:10]=[CH:11][C:12]([O:16][CH3:17])=[C:13]([NH:14][S:29]([C:26]3[CH:25]=[CH:24][C:23]([C:19]4[S:18][CH:22]=[CH:21][CH:20]=4)=[CH:28][CH:27]=3)(=[O:30])=[O:31])[CH:15]=2)[CH2:5]1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1N
Reactant: O=S(=O)(Cl)c1ccc(-c2cccs2)cc1
Solvent: c1ccncc1
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(-c2cccs2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)aniline (D4) (200 mg, 0.85 mmol) in pyridine (5 ml) was treated 4-(2-thienyl)benzenesulfonyl chloride (WO 9827069) (258 mg, 1.0 mmol). The solution was stirred at room temperature for 24 hours and concentrated in vacuo. The residue was co-evaporated with methanol and toluene (×3). The residue was dissolved in dichloromethane and washed with saturated sodium bicarbonate solution. The organic phase was washed with water, brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (1:40 to 1:20 2M ammonia in methanol:dichloromethane) to afford the title product (E17). MS (ES+) m/e 458 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[S:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:43]=[CH:42][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[CH:36]=[C:37]([NH2:41])[CH:38]=[CH:39][CH:40]=5)[O:32][C:33]=4[CH3:34])=[C:25]([O:44][CH3:45])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[N:7]=1)[CH3:2].[CH3:46][S:47](Cl)(=[O:49])=[O:48].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:1]([C:3]1[S:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:43]=[CH:42][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[CH:36]=[C:37]([NH:41][S:47]([CH3:46])(=[O:49])=[O:48])[CH:38]=[CH:39][CH:40]=5)[O:32][C:33]=4[CH3:34])=[C:25]([O:44][CH3:45])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:14]=2)[N:7]=1)[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2OCc2ccc(OCc3nc(-c4cccc(N)c4)oc3C)c(OC)c2)cs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2OCc2ccc(OCc3nc(-c4cccc(NS(C)(=O)=O)c4)oc3C)c(OC)c2)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
A mixture of {3-[4-({4-[({4-[(E)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}amine (100 mg), methanesulfonyl chloride (0.013 mL), triethylamine (0.024 mL) and tetrahydrofuran (1 mL) was stirred at room temperature for 1 hr. The reaction mixture was added to saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate-tetrahydrofuran. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The eluate was subjected to reversed phase HPLC and eluted with acetonitrile-water (10:90-100:0, v/v). The obtained fraction was concentrated, and saturated aqueous sodium hydrogen carbonate was added to the residue. The mixture was extracted with ethyl acetate-tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give N-{3-[4-({4-[({4-[(E)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}methanesulfonamide (37 mg, yield 33%). Recrystallization from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 113-115° C.
Reaction SMILES: [C:1]1(=[O:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.N.[Cl-].[NH4+].[C:20]1(C)C=CC=CC=1>>[CH3:20][CH:14]1[CH2:15][C:1](=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: Cc1ccccc1
Reactant: O=C1C=CCCCCCCCCCCCC1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Product: CC1CCCCCCCCCCCCC(=O)C1
Temperature: -78 °C
Reaction time: 17 h

Procedure:
The solution was cooled to -78° C., and a solution of 0.3604 g (1.62 mmol) of 2-cyclopentadecenone in 1 ml of toluene was added thereto dropwise, followed by stirring at -78° C. for 17 hours. To the reaction mixture was added 4 ml of a 1:1 (by volume) mixture of aqueous ammonia and a saturated ammonium chloride aqueous solution, followed by heating up to room temperature. The aqueous layer was removed, and the organic layer was washed successively with a 1:1 (by volume) mixture of aqueous ammonia and a saturated ammonium chloride aqueous solution, a 5% hydrochloric acid aqueous solution, a saturated sodium chloride aqueous solution, and a saturated sodium carbonate aqueous solution, and dried over sodium sulfate. The toluene was removed by distillation, and the residue was purified by silica gel column chromatography using hexane/ethyl acetate (40:1 by volume) as an eluent and then distilled under reduced pressure to obtain an optically active muscone. The yield, optical rotation, optical purity, and stereochemistry of the product were determined, and the results obtained are shown in Table 1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1([CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[O:9][C:8](=[O:10])[CH2:7][C:6](=[O:11])[CH2:5]1.[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:22][CH2:23][C:24](O)=[O:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:12]1([C:4]2([CH2:3][CH2:2][NH:1][C:24](=[O:25])[CH2:23][CH2:22][C:18]3[O:17][CH:21]=[CH:20][CH:19]=3)[CH2:5][C:6](=[O:11])[CH2:7][C:8](=[O:10])[O:9]2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C(O)CCc1ccco1
Reactant: NCCC1(C2CCCC2)CC(=O)CC(=O)O1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: O=C1CC(=O)OC(CCNC(=O)CCc2ccco2)(C2CCCC2)C1
Yield: 18.7 %

Procedure:
A solution of 6-(2-Amino-ethyl)-6-cyclopentyl-dihydro-pyran-2,4-dione (90 mg, 0.4 mmol) from Step 5 below, TEA (0.22 mL, 1.6 mmol), 3-furan-2-yl-propionic acid (67 mg, 0.48 mmol) and HATU (182 mg, 0.48 mmol) in DMF (2 mL) was stirred at room temperature overnight. The reaction was purified directly by preparatory HPLC to yield the desired product (26 mg, 19% yield).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][N:11]([CH3:15])[CH2:12]2)=[CH:7][CH:6]=1)=[O:4].[Cl:16][C:17]1[CH:25]=[C:24]2[C:20]([C:21]([CH2:38][C:39]([O:41][CH3:42])=[O:40])=C(C(C3N=CC4CCCCC=4C=3)=O)[NH:23]2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:25]=[C:24]2[C:20]([C:21]([CH2:38][C:39]([O:41][CH3:42])=[O:40])=[C:2]([C:3]([C:5]3[CH:14]=[C:13]4[C:8]([CH2:9][CH2:10][N:11]([CH3:15])[CH2:12]4)=[CH:7][CH:6]=3)=[O:4])[NH:23]2)=[CH:19][CH:18]=1
Reactant: CN1CCc2ccc(C(=O)CBr)cc2C1
Reactant: COC(=O)Cc1c(C(=O)c2cc3c(cn2)CCCC3)[nH]c2cc(Cl)ccc12
Product: COC(=O)Cc1c(C(=O)c2ccc3c(c2)CN(C)CC3)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 7-bromoacetyl-2-methyl-1,2,3,4-tetrahydroisoquinoline* and methyl trans-4-chloro-2-[(phenylsulfonyl)amino]cinnamate (Example 1, step 1).
Reaction SMILES: C(O)C.[O:4]1[CH2:9][CH2:8][N:7]([C:10](OCC)=[CH:11][C:12](N2CCOCC2)=[O:13])[CH2:6][CH2:5]1.[S:23]([C:27]1[CH:32]=[CH:31][C:30]([NH:33][NH2:34])=[CH:29][CH:28]=1)([OH:26])(=[O:25])=[O:24].Cl>C(N(CC)CC)C.C(O)(C)C.C(O)(=O)C>[CH2:6]([N:7]([CH2:10][CH3:11])[CH2:8][CH3:9])[CH3:5].[O:4]1[CH2:9][CH2:8][N:7]([C:10]2[NH:34][N:33]([C:30]3[CH:29]=[CH:28][C:27]([S:23]([OH:26])(=[O:24])=[O:25])=[CH:32][CH:31]=3)[C:12](=[O:13])[CH:11]=2)[CH2:6][CH2:5]1
Reactant: CCOC(=CC(=O)N1CCOCC1)N1CCOCC1
Reactant: NNc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: CC(C)O
Product: O=c1cc(N2CCOCC2)[nH]n1-c1ccc(S(=O)(=O)O)cc1
Reaction time: 8 h

Procedure:
Into 70 ml of ethanol was dissolved 13.5 g of β-morpholino-β-ethoxy-acrylic morpholide, and 9.4 g of p-sulfophenyl hydrazine was dissolved in a mixed solution of 30 g of triethylamine and 18 g of glacial acetic acid. The two solutions were then mixed. The resulting mixed solution was boiled on a steam bath for 8 hours. The mixture was then concentrated under reduced pressure to thereby provide a reddish, oily compound, to which 50 ml of isopropyl alcohol and 10 ml of concentrated hydrochloric acid (38 wt%) were added. Upon standing the thus obtained solution in a refrigerator for one night, crystals precipitated. The crystals were collected and recrystallized from ethanol, whereupon 9.8 g of crystals of the objective compound of a melting point of 203° to 205° C. was obtained.
Reaction SMILES: [Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:12]([O-])=O)[CH:3]=1.Cl.[Sn](Cl)[Cl:17]>O>[ClH:17].[NH2:12][C:4]1[CH:3]=[C:2]([Br:1])[C:10]([F:11])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1cc(F)c(Br)cc1[N+](=O)[O-]
Reactant: Cl[Sn]Cl
Agent: Cl
Solvent: O
Product: Nc1cc(Br)c(F)cc1C(=O)O
Temperature: 90 °C
Yield: 83 %

Procedure:
To a mixture of 4-bromo-5-fluoro-2-nitrobenzoic acid (10 g, 37.9 mmol) and HCl (70 mL, 852 mmol) in water (70 mL) was added tin(II) chloride (21.55 g, 114 mmol) and the mixture was then heated at 90° C. for 3 hours. After cooling to RT, the formed precipitate was filtered, washed with water and collected to give title compound (8.51 g). LCMS (A): m/z [(M−HCl)+H]+ 234/236, C7H5BrFNO2.HCl requires 269/271 (acidic).
Reaction SMILES: C(O)C.[H][H].[CH3:6][C:7]1[C:15]2[C:10](=[C:11]([CH2:19][CH3:20])[C:12]([N+:16]([O-])=O)=[CH:13][CH:14]=2)[NH:9][CH:8]=1>[Fe].C(O)(=O)C>[CH3:6][C:7]1[C:15]2[C:10](=[C:11]([CH2:19][CH3:20])[C:12]([NH2:16])=[CH:13][CH:14]=2)[NH:9][CH:8]=1
Reactant: CCc1c([N+](=O)[O-])ccc2c(C)c[nH]c12
Reactant: [H][H]
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: CCc1c(N)ccc2c(C)c[nH]c12
Temperature: 90 °C

Procedure:
A mixture of 0.5 1 of 96° ethanol, 0.5 l of glacial acetic acid and 100 g of hydrogen-reduced pure iron is heated to 90° C. 51 g of 3-methyl-6-nitro-7-ethylindole are added in portions over 15 minutes.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]#[N:18])=[CH:16][C:11]=2[NH:10][C:9]1=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[C:22]([O:26][C:27](=[O:36])[CH:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([CH3:25])([CH3:24])[CH3:23]>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]#[N:18])=[CH:16][C:11]=2[N:10]([CH:28]([C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:36])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:9]1=[O:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1c(=O)[nH]c2cc(C#N)ccc21
Reactant: CC(C)(C)OC(=O)C(Br)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C(c1ccccc1)n1c(=O)n(C(=O)OC(C)(C)C)c2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78.9 %

Procedure:
To a chilled solution of 5-cyano-2-oxo-2,3-dihydro-benzoimidazole-1-carboxylic acid tert-butyl ester (808 mg, 3.1 mmol) in dry DMF (15 mL) was added NaH (60% dispersion mineral oil, 131 mg, 3.3 mmol) under N2 atmosphere. The reaction was stirred at room temperature for 15 min. Then at 0° C., a solution of bromophenylacetic acid tert-butyl ester (887 mg, 3.3 mmol) in DMF (5 mL) was added. The reaction was stirred at room temperature for 2 hours, diluted with ethyl acetate, washed with water, with a saturated NH4Cl aqueous solution, brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography in silica gel using 15% ethyl acetate in n-heptane as eluent to afford 3-(tert-butoxycarbonyl-phenyl methyl)-5-cyano-2-oxo-2,3-dihydro-benzoimidazole-1-carboxylic acid tert-butyl ester (VIIc) (1.1 g, 78%) as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)(=O)[CH3:2].[N:13]1[NH:14][C:15](=[O:19])[CH:16]=CC=1>>[O:19]=[C:15]1[NH:14][N:13]=[C:1]([C:4]2[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=2)[CH:2]=[CH:16]1
Reactant: O=c1cccn[nH]1
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Product: O=C(O)c1ccc(-c2ccc(=O)[nH]n2)cc1

Procedure:
50 g of 4-acetylbenzoic acid are converted into the pyridazinone in accordance with GWP 1.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH:6]([CH3:8])[CH2:5][N:4]([CH2:9][C:10]([OH:28])([CH2:15][C:16]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[O:26][CH3:27])([CH3:18])[CH3:17])[C:11]([F:14])([F:13])[F:12])[CH2:3]1.[CH:29](OC=O)=[O:30].C(N=C=NC(C)C)(C)C.C(O)=O>C(Cl)Cl.N1C=CC=CC=1>[F:25][C:23]1[CH:22]=[CH:21][C:20]([O:26][CH3:27])=[C:19]([C:16]([CH3:18])([CH3:17])[CH2:15][C:10]([OH:28])([C:11]([F:12])([F:13])[F:14])[CH2:9][N:4]2[CH2:3][CH:2]([CH3:1])[N:7]([CH:29]=[O:30])[CH:6]([CH3:8])[CH2:5]2)[CH:24]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CN1CC(C)NC(C)C1)C(F)(F)F
Reactant: O=COC=O
Agent: CC(C)N=C=NC(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O=CO
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CN1CC(C)N(C=O)C(C)C1)C(F)(F)F
Reaction time: 1 h

Procedure:
To a solution of 2-(3,5-dimethylpiperazin-1-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol (20 mg) in methylene chloride (1 mL) at 0° C. was added pyridine (60.7 μL) followed by formic anhydride (2M in methylene chloride, 0.5 mL). (Formic anhydride was freshly prepared by slow addition of one equivalent of 1,3-diisopropylcarbodiimide to 2 equivalents of formic acid in methylene chloride. The resulting suspension was stirred for 1 hour, and filtered). The resulting mixture was stirred overnight for 20 hours, filtered through a cotton plug, poured into half-saturated aqueous sodium bicarbonate solution, and extracted twice with methylene chloride. The combined organic phases were dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel (eluted with 5% methanol-methylene chloride) to give the title compound as a clear oil (19.3 mg).
Reaction SMILES: [CH2:1]([C@H:8]([NH:33][C:34](=[O:44])[O:35][C@@H:36]1[C@H:43]2[C@H:39]([O:40][CH2:41][CH2:42]2)[O:38][CH2:37]1)[C@H:9]([OH:32])[CH2:10][N:11]([CH2:23][C:24]([CH3:31])([CH3:30])[CH2:25][CH2:26][CH2:27][C:28]#[N:29])[S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH3:22])[CH:16]=1)(=[O:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Ni]>[NH2:29][CH2:28][CH2:27][CH2:26][CH2:25][C:24]([CH3:31])([CH3:30])[CH2:23][N:11]([S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH3:22])[CH:16]=1)(=[O:14])=[O:13])[CH2:10][C@@H:9]([OH:32])[C@@H:8]([NH:33][C:34](=[O:44])[O:35][C@@H:36]1[C@H:43]2[C@H:39]([O:40][CH2:41][CH2:42]2)[O:38][CH2:37]1)[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNc1cccc(S(=O)(=O)N(C[C@@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)CC(C)(C)CCCC#N)c1
Agent: [Ni]
Product: CNc1cccc(S(=O)(=O)N(C[C@@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)CC(C)(C)CCCCN)c1
Yield: 70.8 %

Procedure:
A mixture of 0.18 g (0.29 mmol) of (3R,3aS,6aR) hexahydrofuro[2,3-b]furan-3-yl N-[(1S,2R)-1-benzyl-3-((5-cyano-2,2-dimethylpentyl)[3-(methylamino)phenyl]sulfonylamino)-2-hydroxypropyl]carbamate (obtained via a protocol directly analogous to Example (Compound 245)) and approximately 50 mg of Raney nickel (washed with water and then MeOH) in 40 mL of 2M NH3/MeOH was subjected to hydrogenation at 40 psi. After 1.5 hours the vessel was purged with nitrogen, catalyst removed by filtration through celite and the filtrate concentrated to dryness in vacuo. The residue was subjected to flash chromatography (SiO2, 9:1 CH2Cl2, 2M NH3 in MeOH) to afford 0.13 g (72%) of the desired amine as a white foam.
Reaction SMILES: [N+](C1C=CC(C[O:9][C:10]([C:12]2[N:13]3[C@H:16]([S:17][CH:18]=2)[C:15]([CH:20](OC(=O)C)[C:21]2[N:22]=[C:23]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH2:25][N:24]4[CH:32]=2)(Br)[C:14]3=[O:37])=[O:11])=CC=1)([O-])=O.P([O-])([O-])([O-])=O.[OH-].[Na+:46].C(OCC)(=O)C>C1COCC1.C(#N)C.[Zn]>[Na+:46].[N:22]1[C:21](/[CH:20]=[C:15]2\[CH:16]3[N:13]([C:14]\2=[O:37])[C:12]([C:10]([O-:11])=[O:9])=[CH:18][S:17]3)=[CH:32][N:24]2[CH2:25][C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:23]=12
Reactant: CC(=O)OC(c1cn2c(n1)-c1ccccc1C2)C1(Br)C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CS[C@@H]21
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C([O-])C1=CSC2/C(=C\c3cn4c(n3)-c3ccccc3C4)C(=O)N12
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
(5R, 6RS)-6-[(RS)-Acetoxy-(5H-imidazo[2,1-a]isoindol-2-yl)-methyl]-6-bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitro-benzyl ester (1.5 g) was dissolved in THF (21 mL) and acetonitrile (9.8 mL). Freshly activated Zn dust (6 g) and 0.5 M phosphate buffer (pH 6.4, 30.8 mL) were added to the reaction mixture. The reaction vessel was covered with foil to exclude light. The mixture was vigorously stirred for 2 h at room temperature. The mixture was cooled to 9° C., and 1 M NaOH aqueous solution was added to adjust pH to 7.5. The reaction solution was mixed with ethyl acetate and filtered through a pad of Celite. The pad was washed with water and the aqueous layer was separated. The aqueous layer was concentrated to 25 mL under high vacuum at 35° C. The concentrate was applied to Diaion HP-21 (100 mL, Mitsubishi Kasei Co. Ltd.) resin column chromatography. After adsorbing, the column was eluted with water and then with 5–15% acetonitrile-water. The combined fractions was concentrated under high vacuum at 35° C. and lyophilized to give the title compound as a yellow amorphous solid (527 mg, 58%). Mp 170° C. (dec); 1H NMR (400 MHz, D2O) δ 4.62 (s, 2H), 6.27 (s, 1H), 6.56 (s, 1H), 6.78 (s, 1H), 7.22–7.31 (m, 4H), 7.52 (d, 1H, J=6.7 Hz).