Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OO)(=[O:3])C.OO.C(OC(=O)C)(=O)C.[Cl:15][CH2:16][CH2:17][N:18]([CH2:45][CH2:46][Cl:47])[C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH3:43])([CH2:34][NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[C:21]([CH3:44])[CH:20]=1>ClCCl>[C:30]([O:29][C:27](=[O:28])[CH2:26][C:25]([C:22]1[CH:23]=[CH:24][C:19]([N+:18]([O-:3])([CH2:45][CH2:46][Cl:47])[CH2:17][CH2:16][Cl:15])=[CH:20][C:21]=1[CH3:44])([CH2:34][NH:35][C:36]([O:38][C:39]([CH3:40])([CH3:42])[CH3:41])=[O:37])[CH3:43])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(=O)OO
Reactant: Cc1cc(N(CCCl)CCCl)ccc1C(C)(CNC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C
Agent: OO
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: Cc1cc([N+]([O-])(CCCl)CCCl)ccc1C(C)(CNC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
Adapting literature known protocols (Tercel, et al., J. Med. Chem. 1995, 38, 1247-1252; and U.S. Pat. No. 7,399,785), peracetic acid (H3CCO3H) is freshly prepared by adding hydrogen peroxide (H2O2) (1.5 mL of a 35 wt-% aqueous solution, 14.0 mmol) dropwise to acetic anhydride (Ac2O) (1.52 mL, 1.65 g, 16.0 mmol). When the reaction mixture is homogeneous, a solution of tert-butyl 3-[4-[bis(2-chloroethyl)amino]-2-methyl-phenyl]-4-(tert-butoxycarbonylamino)-3-methyl-butanoate (7o) (1.66 g, 3.29 mmol) in dichloromethane (DCM) (20 mL) is added with vigorous stirring at about room temperature for about 2 h. The reaction is followed by TLC and/or LC/MS to completion. The reaction is quenched with 2.0 N hydrochloric acid (HCl), and the aqueous layer separated and repeatedly washed with DCM until the organic extracts are colorless. The aqueous phase is evaporated to dryness under reduced pressure, dried over anhydrous sodium sulfate (Na2SO4), and partially reduced in volume. Diethyl ether (Et2O) is added to separate the title compound 4-[3-tert-butoxy-1-[(tert-butoxycarbonylamino)methyl]-1-methyl-3-oxo-propyl]-N,N-bis(2-chloroethyl)-3-methyl-benzeneamine oxide (25a). The material may be purified by silica gel column chromatography using ethyl acetate (EtOAc), methanol (MeOH), and hexane mixtures.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:30]=[CH:29][C:9]3[N:10]=[C:11]([C@H:13]4[CH2:18][CH2:17][C@H:16]([O:19][CH2:20][C:21](N5CCOCC5)=[O:22])[CH2:15][CH2:14]4)[O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1.[CH3:31][Mg]Br>C1COCC1.C1(C)C=CC=CC=1.C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:30]=[CH:29][C:9]3[N:10]=[C:11]([C@H:13]4[CH2:18][CH2:17][C@H:16]([O:19][CH2:20][C:21](=[O:22])[CH3:31])[CH2:15][CH2:14]4)[O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1
Reactant: O=C(CO[C@H]1CC[C@H](c2nc3ccc(OCC4CC4)cc3o2)CC1)N1CCOCC1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(=O)CO[C@H]1CC[C@H](c2nc3ccc(OCC4CC4)cc3o2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 6-(cyclopropylmethoxy)-2-[trans-4-(2-(morpholin-4-yl)-2-oxoethoxy)cyclohexyl]-1,3-benzoxazole (427 mg) in THF (5 mL) was added a solution (1.5 M, 1.37 mL) of methylmagnesium bromide in toluene/THF under ice-cooling. The reaction mixture was stirred at 0° C. for 1 hr, and extracted with ethyl acetate and 1M hydrochloric acid. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (260 mg).
Reaction SMILES: [OH:1][CH2:2][C@H:3]([CH2:19][CH:20]=[CH2:21])[CH2:4][C@H:5]1[CH2:9][O:8][C:7]([CH3:11])([CH3:10])[N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].N1C=CN=C1.[CH3:27][C:28]([Si:31](Cl)([CH3:33])[CH3:32])([CH3:30])[CH3:29].O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Si:31]([O:1][CH2:2][C@H:3]([CH2:19][CH:20]=[CH2:21])[CH2:4][C@H:5]1[CH2:9][O:8][C:7]([CH3:11])([CH3:10])[N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])([C:28]([CH3:30])([CH3:29])[CH3:27])([CH3:33])[CH3:32]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=CC[C@@H](CO)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: C=CC[C@@H](CO[Si](C)(C)C(C)(C)C)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.7 %

Procedure:
To a solution of (S)-tert-butyl 4-((R)-2-(hydroxymethyl)pent-4-enyl)-2,2-dimethyloxazolidine-3-carboxylate (11.5 g, 38.4 mmol), imidazole (7.84 g, 115.2 mmol) and DMAP (234 mg, 1.92 mmol) in CH2Cl2 (200 mL) was added a solution of TBSCl (8.68 g, 57.6 mmol) in CH2Cl2 (100 mL) dropwise. The reaction mixture was stirred at rt for overnight. Water (100 mL) was added and the aqueous layer was extracted with CH2Cl2 (3×100 mL). The combined organic layers was washed with brine (70 mL), then dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by column chromatography to afford (S)-tert-butyl 4-((R)-2-((tert-butyldimethylsilyloxy)methyl)pent-4-enyl)-2,2-dimethyloxazolidine-3-carboxylate (9 g, 57%).
Reaction SMILES: [Br:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([CH3:13])[C:6]2=[O:12].S(=O)(=O)(O)O.[N+:19]([O-])([OH:21])=[O:20]>>[Br:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([N+:19]([O-:21])=[O:20])=[C:7]2[C:3]=1[CH2:4][N:5]([CH3:13])[C:6]2=[O:12]
Reactant: O=[N+]([O-])O
Reactant: CN1Cc2c(ccc(F)c2Br)C1=O
Agent: O=S(=O)(O)O
Product: CN1Cc2c(Br)c(F)cc([N+](=O)[O-])c2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 28 %

Procedure:
A solution of 4-bromo-5-fluoro-2-methyl-2,3-dihydro-1H-isoindol-1-one (Compound 31F, 1.5 g, 6.1 mmol) in sulfuric acid (3.0 mL, 56 mmol) was cooled in an ice bath to 0° C. and then charged with nitric acid (2.0 mL, 43 mmol). The reaction mixture was allowed to stir overnight while gradually warming to rt. The reaction mixture was quenched by adding the mixture dropwise into a separatory funnel containing ice and then extracted with DCM (15 mL). The organic layer was washed with brine (15 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to a yellow solid. The crude material was purified using a Teledyne ISCO Combiflash® Rf system using DCM/EtOAc (100:0→90:10) as eluent to afford the product compound as a yellow solid (493 mg, 28%). 1H NMR (CDCl3, 400 MHz): δ 7.60 (d, J=7.6 Hz, 1H) 4.39 (s, 2H) 3.23 (s, 3H). MS (ESI): m/z=290.96 [M+H]+. UPLC: tR=1.23 min (UPLC-TOF: polar—3 min).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:15]1[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]1)=[O:5]
Reactant: CN1CCNCC1
Reactant: O=C(Cl)c1ccccc1Br
Solvent: Cc1ccccc1
Product: CN1CCN(C(=O)c2ccccc2Br)CC1
Reaction time: 8 h
Yield: 78.5 %

Procedure:
To a solution of 2-bromobenzoyl chloride (2 g, 9 mmol) in toluene (30 mL) was added N-methylpiperazine (2 mL, 18 mmol, 2 equiv.). The resulting mixture was stirred overnight. The precipitate was filtered and the filtrate was concentrated under reduced pressure. The residue was taken into dichloromethane, washed with water. The organic layer was concentrated under reduced pressure to give 2 g (77% yield) of intermediate 10.
Reaction SMILES: ClC1C=CC2N=C(C)C=CC=2C=1[C:13](O)=[O:14].[NH2:16][C:17](=[N:47][OH:48])[CH2:18][CH2:19][O:20][C@H:21]1[CH2:25][CH2:24][N:23]([C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[C:31]([Cl:46])[C:32]=3[NH:36][C:37](=[O:45])[CH2:38][CH:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)[N:27]=2)[CH2:22]1>>[Cl:46][C:31]1[C:32]([NH:36][C:37](=[O:45])[CH2:38][CH:39]2[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]2)=[C:33]2[C:28](=[CH:29][CH:30]=1)[N:27]=[C:26]([N:23]1[CH2:24][CH2:25][C@H:21]([O:20][CH2:19][CH2:18][C:17]3[NH:16][C:13](=[O:14])[O:48][N:47]=3)[CH2:22]1)[CH:35]=[CH:34]2
Reactant: Cc1ccc2c(C(=O)O)c(Cl)ccc2n1
Reactant: NC(CCO[C@H]1CCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)C1)=NO
Product: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(N3CC[C@H](OCCc4noc(=O)[nH]4)C3)ccc12

Procedure:
Prepared according to the method of Example 102 (b) using N-[2-[(3S)-3-[[3-amino-3-(hydroxyimino)propyl]oxy]-1-pyrrolidinyl]-6-chloro-5-quinolinyl]-cyclohexaneacetamide (Example 108 (a)) (200 mg). Purification (SiO2, methanol:dichloromethane 2:98 as eluant) gave the title compound as a solid (20 mg).
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[CH:8]=[CH:7][S:6][C:5]=1[CH:9]=[O:10]>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:1][C:7]1[S:6][C:5]([CH:9]=[O:10])=[C:4]([CH3:3])[CH:8]=1
Reactant: BrBr
Reactant: Cc1ccsc1C=O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Cc1cc(Br)sc1C=O
Temperature: 25 °C
Yield: 72.7 %

Procedure:
Bromine (104 mL, 2.02 mol) was added dropwise to a 0° C. solution of 255 g of 3-methylthiophene-2-carboxaldehyde (2.02 mol) in 1.7 L of chloroform cooled with an external ice bath. After the addition was complete, the mixture was allowed to slowly warm to room temperature, and then heated at reflux temperature for 2 hours. The red mixture was diluted with 1 L methylene chloride and successively washed with water, saturated bicarbonate solution, and brine. The organic fraction was dried over anhydrous sodium sulfate and concentrated to a red oil. The crude oil was then vacuum distilled to isolate fractions which eluted at 101-106° C. at ca. 2 torr, which produced 301 g of a pale yellow-green solid. 1H NMR (CDCl3, 200 MHz): δ=9.87 (s, 1H), 6.94 (s, 1H) 2.53 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](Br)=[CH:13][C:12]([CH:16]2[O:20][CH2:19][CH2:18][O:17]2)=[C:11]([CH3:21])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.[CH2:33]([O:40][C@@H:41]1[C@@H:47]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C@H:46]([O:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[C@@H:45]([CH2:64][O:65][CH2:66][C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[O:44][C:42]1=[O:43])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:33]([O:40][C@@H:41]1[C@@H:47]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C@H:46]([O:56][CH2:57][C:58]2[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=2)[C@@H:45]([CH2:64][O:65][CH2:66][C:67]2[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=2)[O:44][C:42]1([C:14]1[CH:13]=[C:12]([CH:16]2[O:20][CH2:19][CH2:18][O:17]2)[C:11]([CH3:21])=[CH:10][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[OH:43])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: O=C1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: Cc1cc(OCc2ccccc2)c(Br)cc1C1OCCO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(OCc2ccccc2)c(C2(O)O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1C1OCCO1
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
To a tetrahydrofuran solution (36 mL) of 2-[4-(benzyloxy)-5-bromo-2-methylphenyl]-1,3-dioxolane (5.82 g, 16.6 mmol) was added dropwise under nitrogen atmosphere at −78° C. a 2.67 M n-butyllithium solution in hexane (6.40 mL, 16.6 mmol), and the mixture was stirred for 30 minutes at the same temperature. Then a tetrahydrofuran solution (18 mL) of 2,3,4,6-tetra-O-benzyl-D-glucono-1,5-lactone (8.16 g, 15.1 mmol) was added dropwise, and the mixture was stirred for 20 minutes at the same temperature. To the reaction solution was added a saturated aqueous solution of ammonium chloride, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine, and dried with anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was evaporated under reduced pressure. Thus obtained residue was purified with silica gel column chromatography (hexane:ethyl acetate=3:1 to 2:1) to obtain the title compound (10.7 g, 87%) as a yellow oily compound.
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]([OH:11])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:4][C:5]#[CH:6].N1C=CN=C1.[CH3:18][Si:19]([CH3:22])([CH3:21])Cl.C(=O)(O)[O-].[Na+]>CCCCCC.CN(C)C=O>[F:1][CH:2]([F:12])[C:3]([O:11][Si:19]([CH3:22])([CH3:21])[CH3:18])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:4][C:5]#[CH:6]
Reactant: C[Si](C)(C)Cl
Reactant: C#CCC(O)(CCCC)C(F)F
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: C#CCC(CCCC)(O[Si](C)(C)C)C(F)F
Temperature: 0 °C

Procedure:
A solution of 11.5 g. of 4-difluoromethyl-4-hydroxy-1-octyne and 11.32 g. of imidazole in 45 ml. of dimethylformamide is cooled in an ice bath under nitrogen. A 10.3 ml. portion of trimethylchlorosilane is added using a syringe over a 15 minute period. The mixture is stirred in the ice bath for one hour and then overnight at room temperature. The solution is diluted with hexane and then poured into saturated aqueous sodium bicarbonate solution. The hexane solution is separated, washed with aqueous sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate and the solvents are evaporated to dryness giving the desired product as a colorless liquid.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][N:4]1[C:13]([C:15]1[CH:20]=[C:19]([C:21](=[O:36])[NH:22][S:23]([C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)(=[O:25])=[O:24])[CH:18]=[CH:17][C:16]=1[N:37]1[C:41]([CH3:42])=[C:40]([Cl:43])[C:39]([C:44]([N:46]([CH2:51][CH2:52][CH2:53][CH3:54])[CH2:47][CH2:48][CH2:49][CH3:50])=[O:45])=[N:38]1)=[O:14].[CH3:55][N:56]1[CH2:61][CH2:60][C:59](=O)[CH2:58][CH2:57]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CC(O)C>[CH2:47]([N:46]([CH2:51][CH2:52][CH2:53][CH3:54])[C:44]([C:39]1[C:40]([Cl:43])=[C:41]([CH3:42])[N:37]([C:16]2[CH:17]=[CH:18][C:19]([C:21](=[O:36])[NH:22][S:23]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)(=[O:25])=[O:24])=[CH:20][C:15]=2[C:13]([N:4]2[C@H:3]([CH2:2][NH:1][CH:59]3[CH2:60][CH2:61][N:56]([CH3:55])[CH2:57][CH2:58]3)[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5]2)=[O:14])[N:38]=1)=[O:45])[CH2:48][CH2:49][CH3:50]
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)N2Cc3ccccc3C[C@H]2CN)c(C)c1Cl
Reactant: CN1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)N2Cc3ccccc3C[C@H]2CNC2CCN(C)CC2)c(C)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.1 %

Procedure:
To a solution of 1-(2-((S)-3-(aminomethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-(naphthalen-2-ylsulfonylcarbamoyl)phenyl)-N,N-dibutyl-4-chloro-5-methyl-1H-pyrazole-3-carboxamide (Example 92, 25 mg, 0.032 mmol) in CH2Cl2 (500 μL) and i-PrOH (500 μL) was added 1-methylpiperidin-4-one (4 μL, 0.032 mmol) followed by Na(OAc)3BH (10 mg, 0.049 mmol). The resulting reaction mixture was stirred at room temperature overnight, then quenched with 2 mL of MeOH followed by 2 mL of 1N aq. NaOH solution. The mixture was poured in sat. aq. NH4Cl solution, and the aqueous layer was extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified using preparative HPLC to give the title compound (10 mg, 31%) as a white solid after lyophilization. 1H NMR (CD3OD, mixture of amide rotamers) δ 8.59-8.52 (m, 1H), 8.51-8.45 (m, 0.5H), 8.40-8.34 (m, 0.5H), 8.26-8.12 (m, 1H), 8.06-7.86 (m, 4H), 7.69-7.45 (m, 3H), 7.29-7.20 (m, 3.5H), 7.04-6.91 (m, 0.5H), 5.33-5.21 (m, 0.5H), 5.08-4.94 (m, 0.5H), 4.63-4.53 (m, 0.5H), 4.34-4.23 (m, 1H), 4.17-4.03 (m, 0.5H), 3.54-3.34 (m, 3.5H), 3.22-2.51 (m, 11.5H), 2.43-2.32 (m, 1H), 2.29 (s, 3H), 2.18-1.99 (m, 1H), 1.84-1.67 (m, 1.5H), 1.65-0.85 (m, 12H), 0.81-0.70 (m, 2.5H), 0.69-0.58 (m, 1H); MS(ESI+) m/z 866.4 (M+H)+.
Reaction SMILES: C(NC(C)C)(C)C.[Li][CH2:9][CH2:10][CH2:11][CH3:12].[C:13]([N:20]1[CH2:25][CH2:24][CH:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>C1COCC1>[CH2:29]([O:28][C:26]([C:23]1([CH2:12][CH2:11][CH:10]=[CH2:9])[CH2:24][CH2:25][N:20]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:21][CH2:22]1)=[O:27])[CH3:30]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C=CCCC1(C(=O)OCC)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 76 %

Procedure:
A mixture of THF (160 mL) and diisopropyl amine (9.92 mL, 70.8 mmol, 1.2 eq) was cooled to −78° C. and a 2.5 M solution of n-BuLi in heptanes (28.3 mL, 70.8 mmol, 1.2 equiv.) was added slowly. The solution was stirred for 15 min, warmed to 0° C. for 20 min and cooled back to −78° C. Ethyl N-Bocpiperidine-4-carboxylate (11 mL, 59 mmol, 1 eq.) in 10 mL of THF was added drop-wise and stirred for 40 min before it was warmed to rt. The reaction mixture was stirred for 12 h, transferred to a separatory funnel, quenched with 500 mL of water and extracted with ethyl acetate (2×300 mL). The combined organics were dried over Na2SO4 and concentrated under vacuum to give the title compound as a yellow oil (13.9 g, 76%).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:16][CH:17]([CH2:21][CH2:22][CH3:23])[C:18](O)=[O:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].C(Cl)(=O)C(Cl)=O.[CH3:30][C:31]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:32]=1[NH2:33].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:13][C:12]([C:9]1[CH:8]=[C:7]([S:16][CH:17]([CH2:21][CH2:22][CH3:23])[C:18]([NH:33][C:32]2[C:34]([CH3:38])=[CH:35][CH:36]=[CH:37][C:31]=2[CH3:30])=[O:19])[CH:6]=[C:5]([C:2]([CH3:1])([CH3:4])[CH3:3])[C:10]=1[OH:11])([CH3:14])[CH3:15]
Reactant: Cc1cccc(C)c1N
Reactant: CCCC(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCCC(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)C(=O)Nc1c(C)cccc1C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The title compound of Example 11 (2.3 g, 0.0068 mole) was dissolved in benzene and the solution cooled to +10° C. in an ice bath. A solution of oxalyl chloride (1.14 g, 0.009 mole) in benzene (10 ml) was added dropwise over a period of 20 minutes. The ice bath was removed and the solution stirred at room temperature for 12 hours. The benzene was removed, fresh benzene (10 ml) added and the procedure repeated. The residue was taken up in benzene and a solution of 2,6-dimethylaniline (0.84 g, 0.007 mole) in benzene (25 ml) added over a period of 20 minutes, followed by the dropwise addition of a solution of triethylamine (1 ml). The solution was stirred for 4 hours and the benzene removed. The residue was taken up in ethyl ether (100 ml), stirred, and the white solid filtered. The filtrate was stripped and the product purified by chromatography on silica. The product was recrystallized from ethyl acetate/hexane, filtered and dried, m.p. ca. 137°-139.5° C. Analysis calc. for C27H39NO2S(441.67): Calc.: C, 73.43; H, 8.90; N, 3.17; S, 7.26. Found: C, 73.75; H, 8.90; N, 3.12; S, 7.41.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][CH2:6][C:7]2[CH:8]=[C:9](C3C=C4C(=C(C(N)=O)C=3)NC=C4C3CCN(S(CC)(=O)=O)CC3)[CH:10]=[N:11][CH:12]=2)[CH2:3][CH2:2]1.[CH3:36][C:37]1([CH3:52])[C:41]([CH3:43])([CH3:42])[O:40][B:39](C2C=C(C=O)C=NC=2)[O:38]1.C(N)C(C)C.[BH3-]C#N.[Na+]>>[CH3:3][CH:1]([CH3:2])[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[N:11][CH:10]=[C:9]([B:39]2[O:40][C:41]([CH3:43])([CH3:42])[C:37]([CH3:52])([CH3:36])[O:38]2)[CH:8]=1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cncc(CNCC5CC5)c4)cc23)CC1
Reactant: CC1(C)OB(c2cncc(C=O)c2)OC1(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(C)CN
Product: CC(C)CNCc1cncc(B2OC(C)(C)C(C)(C)O2)c1

Procedure:
Following the general procedure of 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridinyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinecarbaldehyde (30 mg, 0.129 mmol), isobutylamine (0.013 mL, 0.129 mmol), and NaCNBH3 (16 mg, 0.258 mmol) were reacted to give 21 mg of crude (2-methylpropyl){[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine. The crude (2-methylpropyl){[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (30 mg, 0.0723 mmol), potassium carbonate (60 mg, 0.434 mmol), and chloro-2-(dimethylaminomethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(II) (4.4 mg, 0.00723 mmol) to give 12.5 mg of the title compound (35%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:10][C:9](=[O:11])[NH:8][C:5]2=[N:6][CH:7]=1.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH:21]=O)[CH:19]=2)[CH:14]=[N:13]1>>[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH:21]=[C:10]3[C:4]4[C:5](=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=4)[NH:8][C:9]3=[O:11])[CH:19]=2)[CH:14]=[N:13]1
Reactant: O=C1Cc2cc(Br)cnc2N1
Reactant: O=Cc1ccc2cn[nH]c2c1
Product: O=C1Nc2ncc(Br)cc2C1=Cc1ccc2cn[nH]c2c1
Yield: 146.6 %

Procedure:
The title compound (50 mg, 95%) was synthesized as a green solid according to the method described for (E/Z)-3-((3-iodo-1H-indazol-6-yl)methylene)-5-methoxyindolin-2-one using 5-bromo-1H-pyrrolo[2,3-b]pyridin-2(3H)-one (21.3 mg, 0.1 mmol) and 1H-indazole-6-carbaldehyde (14.6 mg, 0.1 mmol). 1H NMR indicated 56:44 mixture of E/Z isomers. E isomer: 1H NMR (400 MHz, DMSO-d6) δ 13.38 (s, 1H, NH), 11.45 (s, 1H, NH), 8.38 (d, J=2.0 Hz, 1H), 8.25 (d, J=2.0 Hz, 1H), 8.19 (s, 1H), 8.01 (s, 1H), 7.93 (s, 1H), 7.90 (d, J=2.0 Hz, 1H), 7.45 (dd, J=8.4 Hz, 2.0 Hz, 1H); Z isomer: δ 13.46 (s, 1H, NH), 11.45 (s, 1H, NH), 8.94 (s, 1H), 8.21 (d, J=2.0 Hz, 1H), 8.19 (s, 1H), 8.15 (s, 1H), 7.99 (dd, J=8.8 Hz, 1.6 Hz, 1H), 7.94 (d, J=8.4 Hz, 1H), 7.85 (d, J=8.0 Hz, 1H); MS ESI 341.0 [M+H]+, calcd for [C15H9BrN4O+H]+ 341.1.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1)[NH2:2].[Cl:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=O)=[CH:12][CH:11]=1.[OH-].[NH4+]>>[Cl:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]2[N:4]3[CH:5]=[CH:6][N:7]=[CH:8][C:3]3=[N:1][N:2]=2)=[CH:12][CH:11]=1
Reactant: NNc1cnccn1
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: [NH4+]
Agent: [OH-]
Product: Clc1ccc(-c2nnc3cnccn23)cc1
Temperature: 110 °C
Reaction time: 18 h

Procedure:
To 2-hydrazinopyrazine (1.60 g, 14.55 mmol) was added 4-chloro-benzoic acid (3 eq) followed by 20 mL of polyphosphoric acid, and the reaction mixture was stirred at 110° C. for 18 h. The hot PPA solution was added to ice and neutralized by the addition of ammonium hydroxide (highly exothermic!). The aqueous solution was extracted with ethyl acetate, washed with brine, and dried over anhydrous sodium sulfate. Concentration followed by flash chromatography (silica gel, 1:1 hexanes: ethyl acetate) afforded 3-(4-chlorophenyl)-[1,2,4]triazolo[4,3-a]pyrazine, as a viscous oil.