Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([CH3:10])[CH:4]=1.C([Li])CCC.CN(C)[C:18](=[O:20])[CH3:19].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([CH2:10][C:18](=[O:20])[CH3:19])[CH:4]=1
Reactant: CC(=O)N(C)C
Reactant: COc1cc(C)nc(C)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cc(C)nc(CC(C)=O)c1
Temperature: 0 °C

Procedure:
To a stirred solution of 4-methoxy-2,6-dimethylpyridine (1.56 g) in tetrahydrofuran (15 ml) was added a solution of n-butyllithium in n-hexane (1.63M, 9.1 ml) dropwise at −50° C. under a nitrogen atmosphere, and the mixture was warmed to 0° C. The mixture was cooled to −50° C., and N,N-dimethylacetamide (1.59 ml) was added dropwise. Then the mixture was warmed to room temperature, poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate (100 ml×2). The combined organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 100 g, n-hexane:ethyl acetate=2:1) to give 1-(4-methoxy-6-methylpyridin-2-yl)propan-2-one (1.75 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].C(O[C@@H](CCN[C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])C(=O)OC1C(F)=C(F)C(F)=C(F)C=1F)(=O)C1C=CC=CC=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:38]([O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39]
Reactant: O=C(NCC[C@H](OC(=O)c1ccccc1)C(=O)Oc1c(F)c(F)c(F)c(F)c1F)OCc1ccccc1
Reactant: O=[N+]([O-])c1ccccc1O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)Oc1ccccc1[N+](=O)[O-]
Yield: 26.3 %

Procedure:
To a stirring solution of 3′,4′,3′″,4′″-tetra-dehydro-3,2′,6′,2′″,6′″-penta-Cbz-neomycin (4, 190 mg, 0.156 mmol) in DMF (2 mL) was added succinimidyl benzoyloxy(2-Cbz-aminoethyl)carbamate (3, 81 mg, 0.18 mmol) and the reaction was stirred under a nitrogen atmosphere. DIPEA (67 μL, 0.38 mmol) was added and the reaction was stirred for 2 days. The reaction mixture was purified on a 2-inch reverse-phase HPLC column, followed by treatment with sat. aq. NaHCO3 to remove the benzoyl protecting group to yield a crude, which was purified on a 1-inch reverse-phase column to yield (5) (60 mg, 0.041 mmol, 26.3% yield): MS m/z (M+Na)+ calc. 1475.5, obs. 1475.4.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[C:18]3[N:17]=[C:16]([C:19]45[CH2:26][CH2:25][C:22]([C:27]([OH:29])=[O:28])([CH2:23][CH2:24]4)[CH2:21][CH2:20]5)[NH:15][C:14]=3[C:13](=[O:30])[N:12]([CH2:31][CH2:32][CH3:33])[C:11]2=[O:34])=[CH:4][CH:3]=1.[OH-].[Na+].[I:37]I>O.C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[C:18]3[N:17]=[C:16]([C:19]45[CH2:20][CH2:21][C:22]([C:27]([OH:29])=[O:28])([CH2:25][CH2:26]4)[CH2:23][CH2:24]5)[NH:15][C:14]=3[C:13](=[O:30])[N:12]([CH2:31][CH2:32][CH3:33])[C:11]2=[O:34])=[CH:4][C:3]=1[I:37]
Reactant: II
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(C(=O)O)(CC3)CC4)nc2n(CCc2ccc(O)cc2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCn1c(=O)c2[nH]c(C34CCC(C(=O)O)(CC3)CC4)nc2n(CCc2ccc(O)c(I)c2)c1=O
Yield: 18.9 %

Procedure:
To a solution of 50 mg 4-{3-[2-(4-Hydroxy-phenyl)-ethyl]-2,6-dioxo-1-propyl-2,3,6,7-tetrahydro-1H-purin-8-yl}-bicyclo[2.2.2]octane-1-carboxylic acid (Example 27a) (0.107 mmol) in water (10 ml) containing 1 eq. of 1N NaOH (110 μL) was added at rt a solution of 30 mg of iodine (0.107 mmol) in ethanol (1 ml). The reaction mixture was concentrated in vacuo and the crude product purified by preparative chromatography to afford 12 mg (20%) of desired product (MH+=592.89).
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[CH2:29]([C:33]1[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=1)[CH2:30][CH2:31][CH3:32]>C1COCC1>[CH2:29]([C:33]1[CH:40]=[CH:39][C:36]([CH:37]=[CH:9][CH2:8][CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3])=[CH:35][CH:34]=1)[CH2:30][CH2:31][CH3:32]
Reactant: O=C(O)CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCc1ccc(C=O)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCCCc1ccc(C=CCCCCC(=O)O)cc1
Yield: 51.3 %

Procedure:
This compound was synthesized from 5-carboxypentyltriphenylphosphonium bromide (9.50 g, 20 mmol) and p-butylbenzaldehyde (3.24 g, 20 mmol) in THF (100 mL) by a Wittig reaction. Kugelrohr distillation yielded the product (2.67 g, 51%) as a colorless oil (bp 154°-157° C./0.05 torr). IR: 3400-2500, 1720 cm-1, 1H-NMR: 0.92 (t, 3H), 1.50 (m, 8H), 2.30 (m, 4H), 2.58 (m, 2H), 5.58+6.15 (m, 1H), 6.38 (t, 1H), 7.18 (m, 4H), 0.30 (bs, 1H). Anal. Calcd. for C17H24O2 : C, 78.42, H, 9.29%; Found: C, 78.38, H, 9.29%. Z:E=62:38.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.Cl.[C:24]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][NH:43][C:44]1[CH:52]=[CH:51][C:47]([C:48](Cl)=[O:49])=[CH:46][CH:45]=1)([O:26][CH3:27])=[O:25]>CCOCC>[C:24]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][NH:43][C:44]1[CH:52]=[CH:51][C:47]([C:48]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:49])=[CH:46][CH:45]=1)([O:26][CH3:27])=[O:25]
Reactant: COC(=O)CCCCCCCCCCCCCCCNc1ccc(C(=O)Cl)cc1
Reactant: C1CCNCC1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COC(=O)CCCCCCCCCCCCCCCNc1ccc(C(=O)N2CCCCC2)cc1
Temperature: 25 °C

Procedure:
To a chilled solution of 35 ml. of piperidine, 2.5 ml. of triethylamine and 0.6 g. of dimethylaminopyridine in 100 ml. of diethyl ether is added (1/2 hour) a solution of 8.3 g. of 4-(15-carbomethoxypentadecylamino)benzoyl chloride hydrochloride in 50 ml. of ether. The solution is warmed to room temperature and maintained there for two hours. The solution is heated to reflux for an additional 2 hours at which time the reaction is complete. The solution is cooled, extracted twice with 100 ml. portions of water and dried over magnesium sulfate. The solvent is removed in vacuo and the solid is recrystallized in 50 ml. of diethyl ether to yield the product.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([O:14][C:15]1[CH:16]=[C:17]([C:24]2[S:25][CH:26]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[N:28]=2)[CH:18]=[CH:19][C:20]=1[O:21][CH2:22][CH3:23])[CH3:13].C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:12]([O:14][C:15]1[CH:16]=[C:17]([C:24]2[S:25][CH:26]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N+:30]=3[O-:9])[N:28]=2)[CH:18]=[CH:19][C:20]=1[O:21][CH2:22][CH3:23])[CH3:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOc1ccc(-c2nc(-c3ccccn3)cs2)cc1OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOc1ccc(-c2nc(-c3cccc[n+]3[O-])cs2)cc1OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.9 %

Procedure:
A solution of 38.5 g of metachloroperbenzoic acid (80%) dissolved in 400 ml of methylene chloride was dropwise added, with ice cooling, to a solution of 49.6 g of 2-(3,4-diethoxyphenyl)-4-(2-pyridyl)thiazole dissolved in 250 ml of methylene chloride. The mixture was stirred at room temperature for 2 hours. To the reaction mixture was added an aqueous sodium hydrogencarbonate solution, followed by separation of layers. The organic layer was washed with an aqueous sodium hydrogencarbonate solution and dried over anhydrous magnesium sulfate. The solvent was removed by distillation. The residue was recrystallized from ethyl acetate to obtain 45.2 g of 2-[2-(3,4-diethoxyphenyl)-4-thiazolyl]pyridine-1-oxide.
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][C:6]([CH2:7][NH:8][C:9](=[O:21])[CH:10]([C:13]2[C:18]([OH:19])=[CH:17][CH:16]=[CH:15][C:14]=2[F:20])[O:11][CH3:12])=[CH:5][CH:4]=1)#[N:2].Br[CH2:25][CH2:26][OH:27].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9](=[O:21])[CH:10]([C:13]2[C:18]([O:19][CH2:25][CH2:26][OH:27])=[CH:17][CH:16]=[CH:15][C:14]=2[F:20])[O:11][CH3:12])=[CH:22][CH:23]=1)#[N:2]
Reactant: OCCBr
Reactant: COC(C(=O)NCc1ccc(C#N)cc1)c1c(O)cccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1c(F)cccc1OCCO

Procedure:
In analogy to example 16.4 (RS)-N-(4-cyano-benzyl)-2-(2-fluoro-6-hydroxy-phenyl)-2-methoxy-acetamide (example 80.4) was reacted with 2-bromoethanol in the presence of cesium carbonat in DMF to give N-(4-cyano-benzyl)-2-[2-fluoro-6-(2-hydroxy-ethoxy)-phenyl]-2-methoxy-acetamide. White solid. MS 359.2([M+H]+)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([OH:19])=O)[CH:15]=3)[C:10]([S:20][CH3:21])=[CH:9]2)=[N:6][CH:7]=1.Cl.[CH3:23][NH:24][CH2:25][C:26]([O:28][CH3:29])=[O:27].CSC1C2C(=CC(C(N3C[C@@H]4C[C@H]3CN4C(OC(C)(C)C)=O)=O)=CC=2)N(C2N=CC(C3C=CC=CN=3)=CN=2)C=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([N:24]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH3:23])=[O:19])[CH:15]=3)[C:10]([S:20][CH3:21])=[CH:9]2)=[N:6][CH:7]=1
Reactant: CNCC(=O)OC
Reactant: CSc1cn(-c2ncc(Br)cn2)c2cc(C(=O)O)ccc12
Agent: CSc1cn(-c2ncc(-c3ccccn3)cn2)c2cc(C(=O)N3C[C@@H]4C[C@H]3CN4C(=O)OC(C)(C)C)ccc12
Agent: Cl
Product: COC(=O)CN(C)C(=O)c1ccc2c(SC)cn(-c3ncc(Br)cn3)c2c1

Procedure:
Amide coupling of 1-(5-bromopyrimidin-2-yl)-3-(methylthio)-1H-indole-6-carboxylic acid (2.0 g, 5.49 mmol) with methyl 2-(methylamino)acetate hydrochloride (1.53 g, 10.9 mmol) analogously to the protocol 244c). White solid. Yield: 0.6 g (24% of theory)
Reaction SMILES: [C:1]([N:8]([CH3:28])[C@H:9]([C:25](O)=[O:26])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[C:30]1([C:36]2([CH2:40][NH2:41])[CH2:39][CH2:38][CH2:37]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:4]([O:3][C:1](=[O:2])[N:8]([C@H:9]([C:25](=[O:26])[NH:41][CH2:40][C:36]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:37][CH2:38][CH2:39]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:13][CH:12]=1)[CH3:28])([CH3:7])([CH3:6])[CH3:5]
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Reactant: NCC1(c2ccccc2)CCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)NCC1(c2ccccc2)CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
A suspension of Boc-NMe-Tyr(OBn)-OH (0.90 g, 2.3 mmol) and C-(1-phenyl-cyclobutyl)-methylamine hydrochloride (synthesized according to the method in Bridges, A. J., Hamilton, H. W., Moos, W. H., Szotek, D. L., N6−substituted Adenosines, U.S. Pat. No. 4,755,594) (0.46 g, 2.3 mmol) and 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) (0.97 g, 5.6 mmol) in methylene chloride (10 mL) was treated with DIEA (0.86 mL, 5.1 mmol). The suspension was stirred at room temperature overnight. The resulting solution was concentrated. The residue was taken up in ethyl acetate. The solution was washed with 0.5 M HCl, saturated NaHCO3, dried over MgSO4, filtered, and concentrated. The oil was chromatographed (CH2Cl2:CH3OH 50:1) to give the desired product (1.07 g, 2.02 mmol; 87% yield). MS-APCI 529 (m+1).
Reaction SMILES: [OH:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH3:12])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Cl:15][C:16]1[C:21]([N:22]([CH3:37])[C:23](=[O:36])[CH2:24][N:25]2[C:29](=[O:30])[C:28]3=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]3[C:26]2=[O:35])=[CH:20][CH:19]=[C:18]([Cl:38])[C:17]=1[CH2:39]OS(C)(=O)=O.O>CN(C)C=O>[Cl:15][C:16]1[C:21]([N:22]([C:23](=[O:36])[CH2:24][N:25]2[C:26](=[O:35])[C:27]3=[CH:34][CH:33]=[CH:32][CH:31]=[C:28]3[C:29]2=[O:30])[CH3:37])=[CH:20][CH:19]=[C:18]([Cl:38])[C:17]=1[CH2:39][O:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH3:12])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN(C(=O)CN1C(=O)c2ccccc2C1=O)c1ccc(Cl)c(COS(C)(=O)=O)c1Cl
Reactant: Cc1nc2c(O)cccc2n1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN4C(=O)c5ccccc5C4=O)c3Cl)cccc2n1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50.5 %

Procedure:
To a suspension of 4-hydroxy-1,2-dimethyl-1H-benzimidazole (250 mg) in N,N-dimethylformamide (2.5 ml) was added sodium hydride (60% in oil, 102 mg) under ice-cooling, and the mixture was stirred for 15 minutes at ambient temperature. To the mixture was added 2,6-dichloro-1-methylsulfonyloxymethyl-3-[N-methyl-N-(phthalimidoacetyl)-amino]benzene (799 mg), and the mixture was stirred for 3 hours at ambient temperature. Water was dropwise added thereto, and the resulting precipitates were collected by filtration to give 4-[2,6-dichloro-3-[N-(phthalimidoacetyl)-N-methylamino]benzyloxy]-1,2-dimethyl-1H-benzimidazole (418 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N:9]1[C:16]2[N:12]([N:13]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[CH:11]=[CH:10]1.FC(F)(F)C(O)=O.[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:38]=[C:39]([CH:43]=[C:44]([S:46]([F:51])([F:50])([F:49])([F:48])[F:47])[CH:45]=2)[C:40](O)=[O:41])[CH2:33][CH2:32]1>>[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:38]=[C:39]([CH:43]=[C:44]([S:46]([F:51])([F:47])([F:48])([F:49])[F:50])[CH:45]=2)[C:40]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([N:9]3[C:16]4[N:12]([N:13]=[C:14]([C:17]5[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=5)[CH:15]=4)[CH:11]=[CH:10]3)[CH:4]=2)=[O:41])[CH2:33][CH2:32]1
Reactant: CN1CCN(c2cc(C(=O)O)cc(S(F)(F)(F)(F)F)c2)CC1
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cccnc3)cc12
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(NC(=O)c2cc(N3CCN(C)CC3)cc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cccnc3)cc12

Procedure:
50 mg (0.17 mmol) of the compound of Example 6A and 79.6 mg (0.17 mmol) of the compound of Example 17A were reacted and worked up analogously to the procedure of Example 16. This gave 82 mg (77% of theory) of the title compound.
Reaction SMILES: FC(F)(F)C1C=CC=C(C(F)(F)F)C=1.[F:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=[O:20].[H][H]>O>[F:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[CH:19]=[O:20]
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: [H][H]
Agent: FC(F)(F)c1cccc(C(F)(F)F)c1
Solvent: O
Product: O=Cc1cccc(F)c1
Temperature: 85 °C
Yield: 57 %

Procedure:
0.5 g of 5% palladium on barium sulfate (recovered from Example 1) and 50 g of 3-fluorobenzoyl chloride were placed in a reaction vessel at room temperature with exclusion of water. A gentle stream of hydrogen gas was then introduced at atmospheric pressure. The mixture was subsequently heated to 80-90° C. and hydrogen gas was introduced continuously at atmospheric pressure. After liberation of acidic offgases had ceased (9.5 hours), the mixture was cooled to room temperature, the catalyst was removed by filtration and the filtrate was distilled at 28 mbar. At a boiling point of 73° C., 3-fluorobenzaldehyde was obtained in a yield of 23.0 g. This corresponds to a yield of 57% of theory.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.[CH2:36]([C:40]1[O:41][C:42]2[CH:48]=[CH:47][C:46](Br)=[CH:45][C:43]=2[CH:44]=1)[CH2:37][CH2:38][CH3:39].C(OCC)(=O)C.CC1CCCCC1>C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH2:36]([C:40]1[O:41][C:42]2[CH:48]=[CH:47][C:46]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:45][C:43]=2[CH:44]=1)[CH2:37][CH2:38][CH3:39]
Reactant: CS(N)(=O)=O
Reactant: CCCCc1cc2cc(Br)ccc2o1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC1CCCCC1
Product: CCCCc1cc2cc(NS(C)(=O)=O)ccc2o1
Temperature: 100 °C

Procedure:
The following are placed in a 20 ml tube predried in an oven: 2 equivalents of base and 1.5 equivalents of methanesulfonamide, 2 mol % of Pd(dba)2 and 5 mol % of 2-(di-tert-butylphosphino)-2′,4′,6′-triisopropyl-1,1′-biphenyl (ligand L1). The tube is stoppered with a septum and placed under an inert atmosphere of argon, and 1 equivalent of 2-n-butyl-5-bromobenzofuran (compound IX or II) dissolved in 10 volumes of solvent is then added by syringe. The reaction medium is then stirred and heated to the reflux point of the solvent or at 100° C. for 24 hours, while monitoring the reaction progress by TLC (eluent: 20/80 ethyl acetate/methylcyclohexane) or by HPLC. At the end of the reaction, the reaction medium is diluted with ethyl acetate and then filtered while hot. The filtrate is then concentrated to give, when cold, crystallization of the desired compound I.
Reaction SMILES: O[CH2:2][C@@H:3]([NH:5][C:6](=[O:9])[O:7][CH3:8])[CH3:4].C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:22]=[N+:23]=[N-:24].[Na+]>ClCCl>[N:22]([CH2:2][C@@H:3]([NH:5][C:6](=[O:9])[O:7][CH3:8])[CH3:4])=[N+:23]=[N-:24]
Reactant: COC(=O)N[C@@H](C)CO
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N[C@@H](C)CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of Intermediate (S)-methyl 1-hydroxypropan-2-ylcarbamate (2.65 g, 20 mmol) and triethylamine (7.0 ml, 50 mmol) in anhydrous dichloromethane (100 mL) was added methanesulfonyl chloride (1.91 mL, 23.9 mmol). The mixture was stirred at rt for 3 h and was then extracted with ethyl acetate. The organic layer was washed with 1N sodium hydroxide solution and brine, and was then dried over sodium sulfate, filtered and concentrated. The crude mesylate product was then dissolved in dry DMF (70 mL) and sodium azide (5.2 g, 80 mmol) was added. The mixture was heated with stirring at 80° C. for 2 h. The cooled reaction mixture was concentrated and the residue was partitioned between ethyl acetate and brine. The organic layer was separated and washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (8:1 hexane/ethyl acetate eluant) to afford (S)-methyl 1-azidopropan-2-ylcarbamate. MS m/z 159.1(M+1).
Reaction SMILES: Br[C:2]1N=C(SC)C(=O)N(C(CC)CC)[CH:7]=1.Br[C:17]1[N:18]=[C:19]([N:29]2[C:37]3[C:32](=[CH:33][C:34]([Cl:39])=[CH:35][C:36]=3[Cl:38])[CH2:31][CH2:30]2)[C:20](=[O:28])[N:21]([CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[CH:22]=1.C([Al](CC)CC)C>>[Cl:39][C:34]1[CH:33]=[C:32]2[C:37](=[C:36]([Cl:38])[CH:35]=1)[N:29]([C:19]1[C:20](=[O:28])[N:21]([CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[CH:22]=[C:17]([CH2:2][CH3:7])[N:18]=1)[CH2:30][CH2:31]2
Reactant: CCC(CC)n1cc(Br)nc(N2CCc3cc(Cl)cc(Cl)c32)c1=O
Reactant: CCC(CC)n1cc(Br)nc(SC)c1=O
Agent: CC[Al](CC)CC
Product: CCc1cn(C(CC)CC)c(=O)c(N2CCc3cc(Cl)cc(Cl)c32)n1

Procedure:
Prepared in a similar fashion as described for XXXII (Example 481, part B) using 5-bromo-3-(5,7-dichloro-2,3-dihydro-1H-indol-1-yl)-1-(1-ethylpropyl)-2(1H)-pyrazinone (Example 507) as the starting material and triethylaluminum in place of trimethylaluminum. mp 136–137° C.; 1H NMR (300 MHz, CDCl3): δ 7.14 (d, J=1.8 Hz, 1 H), 7.09 (d, J=1.8 Hz, 1 H), 6.54 (s, 1 H), 4.90–4.79 (m, 1 H), 4.30 (t, J=8.1 Hz, 2 H), 3.14 (t, J=8.1 Hz, 2 H), 2.44 (q, J=7.4 Hz, 2 H), 1.84–1.69 (m, 2 H), 1.67–1.61 (m, 2 H), 1.18 (t, J=7.5 Hz, 3 H), 0.86 (t, J=7.3 Hz, 6H); HRMS (ESI) calcd for C19H24N3OCl2 (M+H)+: 380.1296; Found m/z 380.1280.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]([O:27][C:28]([N:30]1[CH2:34][CH2:33][C@@H:32]([NH2:35])[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].C(N(C(C)C)CC)(C)C>CC(O)C>[C:23]([O:27][C:28]([N:30]1[CH2:34][CH2:33][C@@H:32]([NH:35][C:18]2[C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=[C:14]3[N:10]([S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:9])=[O:8])[CH:11]=[CH:12][C:13]=23)[CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CC[C@@H](Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)C1
Temperature: 80 °C
Reaction time: 4 h
Yield: 83.9 %

Procedure:
A suspension of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (8.16 g, 24.2 mmol), (R)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester (5.00 g, 26.8 mmol), and diisopropylethylamine (5.14 ml, 29.5 mmol) in propan-2-ol (150 ml) was heated at 80° C. for 13 h. The mixture was then cooled to 25° C. and stirred for 4 h. The resulting yellow solid was collected by vacuum filtration, washed with heptanes (1×20 ml), and was air-dried to afford (R)-3-(1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester (9.90 g, 88%). LCMS (Method G, ESI): RT=1.19 min, m+H=488.3. This material was used in the next step below without additional purification or characterization.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]1([S:11]([N:14]2[C:22]3[C:17](=[C:18]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)(=[O:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(OC(=O)C)(=O)C>[N+:1]([C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[N:14]([S:11]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)(=[O:12])=[O:13])[CH:15]=1)([O-:4])=[O:2]
Reactant: CC(C)(C)OC(=O)Cc1cccc2c1ccn2S(=O)(=O)c1ccccc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Product: CC(C)(C)OC(=O)Cc1cccc2c1c([N+](=O)[O-])cn2S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To acetic anhydride (5 mL) at 0° C. was added 90% nitric acid (0.183 mL, 3.90 mmol) and the resulting mixture was aged for 10 min, then added dropwise to a solution of tert-butyl [1-(phenylsulfonyl)-1H-indol-4-yl]acetate from Step B (1.00 g, 2.69 mmol) in acetic anhydride (5 mL) at −78° C. The reaction mixture was stirred at −78° C. for 6 h, then aged at −20° C. for 16 h, then quenched with H2O and extracted with EtOAc (2×10 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 70:30, to give the title compound. MS: m/z=361 (M−C4H7).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([O:29][C:30]([NH:32][C@@H:33]([C@H:45]([CH3:53])[CH2:46][CH:47]([CH3:52])[CH2:48][CH2:49][CH:50]=[CH2:51])[C:34]([N:36]1[CH2:40][C@H:39]([OH:41])[CH2:38][C@H:37]1[C:42](O)=[O:43])=[O:35])=[O:31])([CH3:28])([CH3:27])[CH3:26].Cl.[NH2:55][C@:56]1([C:61]([O:63][CH3:64])=[O:62])[CH2:58][C@H:57]1[CH:59]=[CH2:60].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:25]([O:29][C:30]([NH:32][C@@H:33]([C@H:45]([CH3:53])[CH2:46][CH:47]([CH3:52])[CH2:48][CH2:49][CH:50]=[CH2:51])[C:34]([N:36]1[CH2:40][C@H:39]([OH:41])[CH2:38][C@H:37]1[C:42]([NH:55][C@:56]1([C:61]([O:63][CH3:64])=[O:62])[CH2:58][C@H:57]1[CH:59]=[CH2:60])=[O:43])=[O:35])=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)OC
Reactant: C=CCCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@]1(C(=O)OC)C[C@H]1C=C
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
HATU (2.510 g, 6.60 mmol) was added to a solution of (2S,4R)-1-((2S,3R)-2-((tert-butoxycarbonyl)amino)-3,5-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylic acid (2.269 g, 5.5 mmol), (1R,2S)-methyl 1-amino-2-vinylcyclopropanecarboxylate HCl (1.172 g, 6.60 mmol), and Hunig's Base (3.84 ml, 22.00 mmol) in DCM (20 ml) and was stirred at RT for overnight. The reaction was washed with 1N HCl (3×) and then brine and evaporated on rotovap, then purified via silica gel chromatography to get the product (1R,2S)-methyl 1-((2S,4R)-1-((2S,3R)-2-((tert-butoxycarbonyl)amino)-3,5-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxamido)-2-vinylcyclopropanecarboxylate (2.68 g, 5.00 mmol, 91% yield) as a light orange foam. MS: MS m/z 558.16 (M++23).