Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CS(O[CH2:18][CH2:19][C@:20]1([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:37])[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH:34]([CH3:36])[CH3:35])[CH:28]=2)[CH2:21]1)(=O)=O.C(#N)C>>[Cl:45][C:40]1[CH:39]=[C:38]([C@:20]2([CH2:19][CH2:18][N:10]3[CH2:11][CH2:12][N:7]([CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:8][CH2:9]3)[CH2:24][CH2:23][N:22]([C:25](=[O:37])[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH:34]([CH3:35])[CH3:36])[CH:28]=3)[CH2:21]2)[CH:43]=[CH:42][C:41]=1[Cl:44]
Reactant: CC(C)Oc1cccc(CC(=O)N2CC[C@](CCOS(C)(=O)=O)(c3ccc(Cl)c(Cl)c3)C2)c1
Reactant: C1CCC(N2CCNCC2)CC1
Solvent: CC#N
Product: CC(C)Oc1cccc(CC(=O)N2CC[C@@](CCN3CCN(C4CCCCC4)CC3)(c3ccc(Cl)c(Cl)c3)C2)c1

Procedure:
In 30 ml of acetonitrile (S)-3-(2-methanesulfonyloxyethyl)-3-(3,4-dichlorophenyl)-1-[(3-isopropoxyphenyl)acetyl)pyrrolidine (3.17 g), prepared as described, Supra, is mixed with an equimolar amount of 1-cyclohexylpiperazine. The reaction mixture is then heated to reflux and refluxed for about ten hours. The mixture is then concentrated under vacuum and the residue is taken up in methylene chloride and washed with a 3N solution of hydrochloric acid, followed by a wash with brine. The organic fraction is dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue precipitates from an acetone/diethyl ether mixture to give the desired title product.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9](/[CH:11]=[CH:12]/[C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:3]=1.[CH3:29][N:30]1[C:35](=[O:36])[N:34]([CH3:37])[C:33]2[CH:38]=[CH:39][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:41][C:32]=2[S:31]1(=[O:52])=[O:51]>>[CH3:29][N:30]1[C:35](=[O:36])[N:34]([CH3:37])[C:33]2[CH:38]=[CH:39][C:40]([C:2]3[N:7]4[CH:8]=[C:9](/[CH:11]=[CH:12]/[C:13]5[CH:22]=[CH:21][C:20]6[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=6)[N:14]=5)[N:10]=[C:6]4[C:5]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[N:4][CH:3]=3)=[CH:41][C:32]=2[S:31]1(=[O:51])=[O:52]
Reactant: CN1C(=O)N(C)S(=O)(=O)c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: Brc1cnc(N2CCOCC2)c2nc(/C=C/c3ccc4ccccc4n3)cn12
Product: CN1C(=O)N(C)S(=O)(=O)c2cc(-c3cnc(N4CCOCC4)c4nc(/C=C/c5ccc6ccccc6n5)cn34)ccc21

Procedure:
Compound 2b was subjected to Suzuki coupling conditions using the methods described in Example 1, Step G, with compound 41b to obtain the title compound 20. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.35 (d, J=8.6 Hz, 1H), 8.18-8.20 (m, 2H), 8.15 (dd, J=8.6, 2.0 Hz, 1H), 7.96 (t, J=8.6 Hz, 2H), 7.90 (s, 1H), 7.86 (d, J=6.6 Hz, 1H), 7.72-7.80 (m, 2H), 7.64 (d, J=16.2 Hz, 1H), 7.56 (t, J=7.3 Hz, 1H), 7.49 (s, 1H), 4.31 (m, 4H), 3.80-3.86 (m, 4H), 3.58 (s, 3H), 3.28 (s, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C30H27N7O4S: 582.2 (M+H). Found 582.4.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[N:13]=2)[N:8]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:7]=1[CH3:35])=[O:5])C.[OH-].[Na+].Cl>C1COCC1>[CH3:35][C:7]1[N:8]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:32])([CH3:34])[CH3:33])[C:9]2=[N:10][CH:11]=[C:12]([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[N:13]=[C:14]2[C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1c(C)n(COCC[Si](C)(C)C)c2ncc(-c3cc(OC)c(OC)c(OC)c3)nc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(-c2cnc3c(n2)c(C(=O)O)c(C)n3COCC[Si](C)(C)C)cc(OC)c1OC
Temperature: 60 °C

Procedure:
To a solution of 6-Methyl-2-(3,4,5-trimethoxy-phenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ethyl ester (110 mg, 0.22 mmol) in 1.0 mL of THF was added a 500 uL of 5.0 M aqueous NaOH. Heated to 60° C. for 3 days. Diluted with THF, made acidic with 1.0 M HCl and partitioned into methylene chloride. Dried the organic phase over Na2SO4, filtered, and concentrated. Collect 107 mg of 6-Methyl-2-(3,4,5-trimethoxy-phenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid sufficiently pure for the next step.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23](Br)[CH:24]=2)[NH:19][CH:18]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:27]([S:29]([CH2:32][CH3:33])(=[O:31])=[O:30])=[CH2:28].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([CH:28]=[CH:27][S:29]([CH2:32][CH3:33])(=[O:31])=[O:30])[CH:24]=2)[NH:19][CH:18]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CS(=O)(=O)CC
Reactant: O=C(OCc1ccccc1)N1CCC[C@@H]1Cc1c[nH]c2ccc(Br)cc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)C=Cc1ccc2[nH]cc(C[C@H]3CCCN3C(=O)OCc3ccccc3)c2c1
Yield: 72.2 %

Procedure:
A stirred mixture of 3-(N-benzyloxycarbonyl-2(R)-pyrrolidinylmethyl)-5-bromo-1H-indole (Preparation 2; 0.43 g, 1.04 mmol), ethyl vinyl sulphone (0.17 g, 1.4 mmol), tri-o-tolylphosphine (91 mg), palladium(II) acetate (16 mg), triethylamine (0.31 ml) and acetonitrile (4 ml), under nitrogen, was heated under reflux for 18 hours, allowed to cool, then evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a dichloromethane to dichloromethane:ethanol (99:1) gradient, to afford the title compound as a foam (0.34 g). Rf 0.80 (SS 2). [α]D25 -50° (c=0.1, CH3OH). Found: C,65.16; H,6.17; N,5.97. C25H28N2O4S; 0.125 CH2Cl2 requires C,65.15; H,6.15; N,6.05%. δ(CDCl3)--mixture of rotamers: 1.42(3H,t), 1.70-1.88(4H,m), 2.78(1H,m), 3.05-3.48(5H,m), 4.20(1H,m), 5.16-5.28(2H, br q), 5.30(0.25H,s,CH2Cl2), 6.64-7.82(1H,m), 6.96 and 7.05(1H, 2×s), 7.30-7.45(7H,m), 7.55-7.80 and 8.00(2H, m and s), 8.32(1H,br s).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:7]=1.[CH2:12]([O:14][C:15]([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])[C:16]#[CH:17])[CH3:13].C(N(CC)CC)C>Cl[Pd](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.[Cu]I.ClCCl>[CH3:11][S:8]([C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:17]#[C:16][C:15]([O:18][CH2:19][CH3:20])([O:14][CH2:12][CH3:13])[O:21][CH2:22][CH3:23])[CH:7]=1)(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1cncc(Br)c1
Reactant: C#CC(OCC)(OCC)OCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(C#Cc1cncc(S(C)(=O)=O)c1)(OCC)OCC
Temperature: 25 °C
Yield: 87.3 %

Procedure:
A solution of 3-bromo-5-methanesulfonyl-pyridine (1.00 g, 4.20 mmol), 3,3,3-triethoxypropyne (1.75 g, 9.4 mmol), dichlorobis(triphenylphospine)palladium(II) (0.15 g, 0.21 mmol), copper(I)iodide (0.08 g, 0.42 mmol), triethylamine (1.80 mL, 12.7 mmol) and dichloromethane (40 mL) was heated at reflux for 48 h. The mixture was cooled to room temperature and the solvent was removed under reduced pressure. The crude product was chromatographed on silica (30% ethyl acetate/hexanes) to give the title compound (1.2 g, 87% yield) as yellow solid. 1H NMR (CDCl3) δ 9.08(d, 1H, J=2.4 Hz), 8.91 (d, 1H J=2.0), 8.28 (t, 1H, J=2.0 Hz), 3.75 (q, 6H, J=7.2), 3.13 (s, 3H), 1.29 (t, 9H, J=7.2).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH:11]([N:14]([CH2:16][CH2:17][O:18][CH3:19])[CH3:15])[CH2:12][CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[NH2:20].Cl[C:22]1[N:27]=[C:26]([NH:28][C@@H:29]2[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]2[NH:35][S:36]([CH3:39])(=[O:38])=[O:37])[C:25]([Cl:40])=[CH:24][N:23]=1>>[Cl:40][C:25]1[C:26]([NH:28][C@@H:29]2[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]2[NH:35][S:36]([CH3:39])(=[O:38])=[O:37])=[N:27][C:22]([NH:20][C:4]2[CH:5]=[CH:6][C:7]3[CH2:13][CH2:12][CH:11]([N:14]([CH2:16][CH2:17][O:18][CH3:19])[CH3:15])[CH2:10][CH2:9][C:8]=3[C:3]=2[O:2][CH3:1])=[N:23][CH:24]=1
Reactant: COCCN(C)C1CCc2ccc(N)c(OC)c2CC1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Product: COCCN(C)C1CCc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)c(OC)c2CC1
Yield: 42.5 %

Procedure:
In an analogous manner to Experimental 691, part c, 1-methoxy-N*7*-(2-methoxyethyl)-N*7*-methyl-6,7,8,9-tetrahydro-5H-benzocycloheptene-2,7-diamine and N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide were combined to yield N-[(1R,2R)-2-(5-Chloro-2-{1-methoxy-7-[(2-methoxy-ethyl)-methyl-amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino}-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (185 mg, 42.5% yield) as a brown foam. 1H-NMR (CDCl3) δ 7.94 (s, 1H), 7.89 (d, J=7.8 Hz, 1H), 6.88 (d, J=8.2 Hz, 1H), 5.41 (m, 1H), 3.91 (m, 1H), 3.73 (s, 1H), 3.45 (m, 2H), 3.32 (m, 5H), 2.78 (m, 7H), 2.30-2.08 (m, 7H), 1.83 (br s, 2H), 1.33 (m, 7H). LC/MS (ESI+)=581 (M+H).
Reaction SMILES: C(O[C:6]([N:8](C)[CH2:9][CH2:10][CH:11]1[O:16][CH2:15][CH2:14][N:13]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)=[O:18])[CH2:12]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:6][NH:8][CH2:9][CH2:10][CH:11]1[O:16][CH2:15][CH2:14][N:13]([C:17]([O:19][CH2:20][C:21]2[CH:22]=[C:23]([Cl:28])[CH:24]=[C:25]([Cl:27])[CH:26]=2)=[O:18])[CH2:12]1
Reactant: CN(CCC1CN(C(=O)OCc2cc(Cl)cc(Cl)c2)CCO1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCCC1CN(C(=O)OCc2cc(Cl)cc(Cl)c2)CCO1

Procedure:
A mixture comprising of 3,5-dichlorobenzyl 2-(2-((tert-butoxycarbonyl)(methyl)amino)ethyl)morpholine-4-carboxylate (step 1) (0.9984 g, 2.232 mmol) and triflouroacetic acid (6.88 ml, 89 mmol) in DCM (7.44 ml) was stirred at room temperature for 1 hour. The reaction mixture was diluted with DCM (7.44 ml) and washed with water followed by sat NaHCO3. The organic portion was separated, dried over MgSO4, filtered and concentrated under reduced pressure to afford the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:28])[C:7](=[C:14]([NH:16][C@@H:17]1[C@@H:23]([OH:24])[C@H:22]([OH:25])[C@@H:21]([CH2:26][OH:27])[O:20][CH:18]1[OH:19])[CH3:15])[C:8]2=[O:13])([O-:3])=[O:2].C(O[C:33](=[O:35])[CH3:34])(=O)C>N1C=CC=CC=1>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:28])[C:7](=[C:14]([NH:16][C@@H:17]1[C@@H:23]([O:24][C:8](=[O:13])[CH3:7])[C@H:22]([O:25][C:18](=[O:19])[CH3:17])[C@@H:21]([CH2:26][O:27][C:33](=[O:35])[CH3:34])[O:20][C@@H:18]1[OH:19])[CH3:15])[C:8]2=[O:13])([O-:3])=[O:2]
Reactant: CC(N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O)=C1C(=O)c2cccc([N+](=O)[O-])c2C1=O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@H](O)[C@H](NC(C)=C2C(=O)c3cccc([N+](=O)[O-])c3C2=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
A mixture of 2-Deoxy-2-[1-(4-nitro-1,3-dioxoindan-2-ylidene)ethylamino]-D-glucopyranose (100 mg, 0.23 mmol), pyridine (2 ml) and acetic anhydride (3 ml) stirred at room temperature overnight. The reaction mixture was evaporated, and the residue was purified by chromatography using CHCl3/EtOAc 10:4 as the mobile phase to give 2-Deoxy-2-[1-(4-nitro-1,3-dioxoindan-2-ylidene)-ethylamino]-3,4,6-tri-O-acetyl-α-D-glucopyranose (23) (165 mg, 79%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[C@@H:14]3[CH2:15][C@@H:11]([CH:12]=[CH:13]3)[C@@H:10]2[C:16]([NH2:18])=[O:17])[C:5]([Cl:19])=[CH:4][N:3]=1.[CH3:20][O:21][C:22]1[C:23]([NH2:41])=[CH:24][C:25]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH2:28][CH2:27][C:26]=2[CH:40]=1>>[Cl:19][C:5]1[C:6]([NH:8][C@@H:9]2[C@@H:14]3[CH2:15][C@@H:11]([CH:12]=[CH:13]3)[C@@H:10]2[C:16]([NH2:18])=[O:17])=[N:7][C:2]([NH:41][C:23]2[C:22]([O:21][CH3:20])=[CH:40][C:26]3[CH2:27][CH2:28][N:29]([CH2:32][CH2:33][N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)[CH2:30][CH2:31][C:25]=3[CH:24]=2)=[N:3][CH:4]=1
Reactant: COc1cc2c(cc1N)CCN(CCN1CCOCC1)CC2
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)n1)CCN(CCN1CCOCC1)CC2
Yield: 13 %

Procedure:
In an analogous manner to Example 1503, the product was prepared from (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 8-Methoxy-3-(2-morpholin-4-yl-ethyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ylamine. Product was isolated as a white foam (15 mg, 13%). MS (ESI+): 568 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.20 (s, 1H), 7.91 (s, 1H), 7.40 (s, 1H), 6.66 (s, 1H), 6.55 (d, J=8 Hz, 1H), 6.32 (s, 2H), 5.56 (br s, 1H), 5.29 (br s, 1H), 4.47 (t, J=8 Hz, 1H), 3.88 (s, 3H), 3.74 (t, J=4.5 Hz, 4H), 3.09 (s, 1H), 2.89 (br s, 5H), 2.71 (br s, 6H), 2.57-2.52 (m, 7H), 2.27 (d, J=9 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[S:12][CH:13]=[CH:14][N:15]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28](B(O)O)[CH:27]=1.C(#N)C.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:2]2[CH:3]=[C:4]3[C:10]([C:11]4[S:12][CH:13]=[CH:14][N:15]=4)=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)[CH:27]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nccs3)c3cc(Br)cnc32)cc1
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: c1cncc(-c2cnc3[nH]cc(-c4nccs4)c3c2)c1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 76.1 %

Procedure:
A mixture of 2-(5-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine-3-yl)thiazole (75 mg, 0.17 mmol), pyridine-3-ylboronic acid (27 mg, 0.22 mmol) 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)-dichloride dichloromethane adduct (6.9 mg, 0.009 mmol), acetonitrile (1 mL) and saturated aqueous NaHCO3 (1 mL) were stirred in a sealed microwave tube at 140° C. for 30 minutes. The mixture was then cooled to room temperature, diluted with ethyl acetate, washed with brine and concentrated to dryness. Silica gel chromatography afforded 2-(5-(pyridine-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl)thiazole (36 mg, 76% yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 7.47 (m, 1H), 7.56 (d, J=3.5 Hz, 1H), 7.81 (d, J=3.5 Hz, 1H), 8.10 (m, 1H), 8.24 (s, 1H), 8.55 (dd, J=2.0, 5.0 Hz, 1H), 8.61 (d, J=2.5 Hz, 1H), (d, J=2.0 Hz, 1H), 8.89 (m, 1H), 12.37 (s, 1H). MS: m/z 279.0 (M+H+)
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=C(Cl)C=C(C(OO)=[O:22])C=1.C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[N+:8]=2[O-:22])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cccc(-c2ccccc2)n1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1cccc(-c2ccccc2)[n+]1[O-]
Temperature: 25 °C

Procedure:
While stirring at room temperature, 4.8 g (28.5 mmol) of 2-phenyl-6-methyl-pyridine were dissolved in 50 ml of chloroform after which a solution of 7.8 g of 75% mCPBA (33.9 mmol) in 75 ml of chloroform were added dropwise. The reaction mixture showed only a slight rise in temperature. After stirring for 1.5 hr, the reaction mixture was shaken twice with 5% aqueous NaHCO3 solution and twice with an aqueous solution of Na2S2O3 to remove the excess of mCPBA, after which the reaction mixture proved to be negative on wet Kl/starch paper, The organic layer was dried on MgSO4. Removal of the drying agent by filtration and solvent by evaporation in vacuo yielded an oil which crystallized upon scratching to give 5.5 g (105%) of crude of 2-phenyl-6-methyl-pyridine-N-oxide, which was employed in the next step without further purification.
Reaction SMILES: [O:1]1[CH2:20][CH:2]1[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:14]3[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=3[O:12][N:11]=2)[CH2:6][CH2:5]1.[NH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][CH2:22]1.[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35]>C(O)(C)C.C(O)C>[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35].[F:19][C:17]1[CH:16]=[CH:15][C:14]2[C:10]([CH:7]3[CH2:6][CH2:5][N:4]([CH:3]([CH:23]4[CH2:24][C:25]5[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=5)[NH:21][CH2:22]4)[CH:2]([OH:1])[CH3:20])[CH2:9][CH2:8]3)=[N:11][O:12][C:13]=2[CH:18]=1.[F:19][C:17]1[CH:16]=[CH:15][C:14]2[C:10]([CH:7]3[CH2:6][CH2:5][N:4]([CH:3]([CH:23]4[CH2:24][C:25]5[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=5)[NH:21][CH2:22]4)[CH:2]([OH:1])[CH3:20])[CH2:9][CH2:8]3)=[N:11][O:12][C:13]=2[CH:18]=1
Reactant: c1ccc2c(c1)CCCN2
Reactant: Fc1ccc2c(C3CCN(CC4CO4)CC3)noc2c1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: CC(C)O
Product: CC(O)C(C1CNc2ccccc2C1)N1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A stirred mixture of N-(2,3-epoxypropyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (2.41 g, 8.73 mmol), 1,2,3,4-tetrahydroquinoline (1.33 g, 10 mmol, in isopropyl alcohol (50 ml) was heated at reflux for 6 hours. The solution was cooled and the solvent was removed on a rotary evaporator. The crude solid was purified by flash chromatography over a silica gel column (SiO2, 40 g, eluted with methylene chloride DCM, and 1-3% MEOH in DCM). The product thus purified weighed 2.0 g. This material was dissolved in ethanol and was treated with a solution of fumaric acid (567 mg, 1.0 eq) in ethanol. The solids collected were recrystallized again from ethanol (50 ml) to yield 1.0 g of white crystals, as a hemifumarate, m.p. 170°-171° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:8][CH2:7][CH2:6][C:5]2[C:9]([NH:18]C(=O)C)=[C:10]([Cl:17])[CH:11]=[C:12]([C:13]([O:15]C)=[O:14])[C:4]=2[O:3]1.[OH-].[Na+]>CO>[CH3:1][C:2]1([CH3:22])[CH2:8][CH2:7][CH2:6][C:5]2[C:9]([NH2:18])=[C:10]([Cl:17])[CH:11]=[C:12]([C:13]([OH:15])=[O:14])[C:4]=2[O:3]1
Reactant: COC(=O)c1cc(Cl)c(NC(C)=O)c2c1OC(C)(C)CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CCCc2c(N)c(Cl)cc(C(=O)O)c2O1

Procedure:
To a solution of 5.46 g (16.8 mmol) of methyl 2,2-dimethyl-6-acetylamino-7-chloro-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylate in 10 ml of methanol is added 10 ml of a 10% aqueous sodium hyroxide solution in a single portion at room temperature. The solution is heated to reflux and refluxing maintained for 2 hours. After cooling, methanol is removed in vacuo and the residue is diluted with water. The pH of this solution is adjusted to 7 with 1N HCl. The neutral solution is extracted with CH2Cl2 and the combined organic extracts are dried over MgSO4, filtered and concentrated. Flash chromatography (30% EtOAc/hexanes) provides 2,2-dimethyl-6-amino-7-chloro-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][C:5]2[NH:6][C:7]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.Br[C:19](=[C:21]([CH3:23])[CH3:22])[CH3:20].II.[Mg]>C1COCC1.C(Cl)Cl>[Cl:17][C:16]1[C:2]([Cl:1])=[CH:3][C:4]2[NH:8][C:7]([C:9]([OH:14])([C:19]([CH3:20])=[C:21]([CH3:23])[CH3:22])[C:10]([F:13])([F:11])[F:12])=[N:6][C:5]=2[CH:15]=1
Reactant: O=C(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Reactant: CC(C)=C(C)Br
Agent: II
Agent: [Mg]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)=C(C)C(O)(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 1-(5,6-dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (577 mg) in THF (5 mL) at 0° C. was added Grignard reagent, which was freshly prepared from 2-bromo-3-methyl-2-butene (1.73 mL), a small iodine flake, and magnesium powder (347 mg) in THF (5 mL). The resulting mixture was stirred at room temperature for 3 hr. The reaction was quenched with NH4Cl (sat. aq), filtered through a pad of Celite®, rinsed with EtOAc, the layers were separated, the aqueous layer extracted with EtOAc, dried over Na2SO4, filtered, and concentrated to yield a residue. The residue was purified by flash chromatography with Biotage 40s+ column and elution with 10%-40% EtOAc/hexanes to yield a yellow solid. The yellow solid was dissolved in a minimal amount of CH2Cl2 and triturated with hexanes to yield the title compound as an off-white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][C:2]1=[O:8].[Br:9]Br.ClCCl>C(O)(=O)C>[Br:9][CH:3]1[C:4](=[O:7])[CH2:5][CH2:6][NH:1][C:2]1=[O:8]
Reactant: O=C1CCNC(=O)C1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C1CCNC(=O)C1Br
Temperature: 25 °C
Reaction time: 1.17 h

Procedure:
To a mixture of piperidine-2,4-dione (0.072 g, 0.637 mmol) in acetic acid (1.591 mL) was added bromine (0.033 mL, 0.637 mmol) dropwise. The reaction mixture was stirred at rt 70 min. Dichloromethane was added and the cloudy mixture was concentrated in vacuo. The residual solution was treated with ethyl ether. A white solid crashed out and the AcOH/ether was decanted. The white solid, presumed to be product was carried forward. The white solid started liquifying and turning red rapidly upon exposure to light and standing.
Reaction SMILES: [CH2:1]([S:5]([C:8]1[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=1)(=[O:7])=[O:6])[CH:2]([CH3:4])[CH3:3].[NH2:17][C@@H:18]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:19]([NH2:21])=[O:20]>>[C:19]([C@@H:18]([NH:17][C:14]([C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([S:5]([CH2:1][CH:2]([CH3:3])[CH3:4])(=[O:6])=[O:7])[N:13]=1)=[O:16])[CH2:22][CH:23]([CH3:25])[CH3:24])(=[O:20])[NH2:21]
Reactant: CC(C)C[C@H](N)C(N)=O
Reactant: CC(C)CS(=O)(=O)c1cccc(C(=O)O)n1
Product: CC(C)C[C@H](NC(=O)c1cccc(S(=O)(=O)CC(C)C)n1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(isobutylsulfonyl)picolinic acid and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials. MS (EI): m/e=356.2 [M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][C:7]#[N:8])[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC.C1COCC1>[S:1]1[CH:5]=[C:4]([CH2:6][CH2:7][NH2:8])[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2
Reactant: N#CCc1csc2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: NCCc1csc2ccccc12
Yield: 24.4 %

Procedure:
Reduce benzo[b]thiophen-3-yl-acetonitrile (350.9 mg, 2.0 mmol) in Et2O (6.0 mL) with 1.0 M LAH in THF (6.0 mL) at 0-10° C. for 1 hour. Carry out Fieser work-up to remove the LAH. Concentrate and pass through an SCX column washing with MeOH and then eluting with 2.0 M NH3 in MeOH. Concentrate the eluant and purify twice by chromatography, eluting with 75:20:5 EtOAc/hexanes/2.0 M NH3 in MeOH and then with 70:20:10 EtOAc/hexanes/2.0 M NH3 in MeOH to yield the title compound (86.5 mg, 24%): MS ES+ 178.2 (M+H)+, 161.2 (base peak); 1H NMR (DMSO-d6) δ 7.94 (d, J=7.3 Hz, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.40-7.33 (m, 3H), 3.32 (br s, 2H), 2.88 (br s, 4H).