Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]([S:17]([C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)(=[O:19])=[O:18])[C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[NH:12][C:11]([C:14]([NH2:16])=O)=[CH:10]2)([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>O1CCCC1>[CH:1]([N:4]([S:17]([C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)(=[O:19])=[O:18])[C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[NH:12][C:11]([C:14](=[S:34])[NH2:16])=[CH:10]2)([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)N(c1cccc2cc(C(N)=O)[nH]c12)S(=O)(=O)c1cccs1
Solvent: C1CCOC1
Product: CC(C)N(c1cccc2cc(C(N)=S)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 70 °C
Reaction time: 1 h
Yield: 74.1 %

Procedure:
A mixture of 7-[isopropyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (320 mg), Lawesson's reagent (213 mg) and tetrahydrofuran (5 ml) was stirred at 70° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from methylene chloride-toluene mixture, and washed with hexane to give the title compound (148 mg, yield 44%) as crystals. melting point 204-205° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][O:39][CH2:40][CH2:41][NH:42][CH3:43]>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:42]([CH2:41][CH2:40][O:39][CH3:38])[CH3:43])[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Reactant: CNCCOC
Product: COCCN(C)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and (2-methoxy-ethyl)-methylamine according to conditions described in general procedure C. Mp: 96-98° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.90-3.15 (m, 4 H), 3.27 (t, J=4.8 Hz, 4 H), 3.20-3.40 (m, 6 H), 3.77 (t, J=4.8 Hz, 4 H), 6.28 (s, 1H), 7.05 (d, J=12.4 Hz, 1H), 7.27 (d, J=8.7 Hz, 1H), 7.43-7.62 (m, 5 H), 7.82 (s, 1H), 8.00 (d, J=7.7 Hz, 1H), 8.26 (d, J=5.1Hz, 1H), 10.47 (s, 1H).
Reaction SMILES: [CH2:1]([C@@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[NH:6][C:5]1=[O:24])[CH:2]=[CH2:3].[H-].[Na+].Br[CH2:28][CH2:29][CH3:30]>CN(C=O)C>[CH2:1]([C@@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([CH2:28][CH2:29][CH3:30])[C:5]1=[O:24])[CH:2]=[CH2:3]
Reactant: CCCBr
Reactant: C=CC[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CC[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CCC)C1=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of (3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one (Example 42, Step A) (70 mg, 0.19 mmol) in 430 μL of DMF was added sodium hydride (60% suspension in mineral oil, 20 mg, 0.51 mmol) at 0° C. The reaction was stirred at 0° C. for 15 min and then treated with 1-bromopropane (53 μL, 0.58 mmol). After being stirred at 25° C. for 4 h, the reaction was quenched with sat. aqueous NaHCO3 and extracted (2×EtOAc). The combined organic layers were washed with sat. aq. NaCl and NaHCO3-solutions, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification of the residue by silica gel prep plate (25% EtOAc/hexanes) provided the title compound as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:57]=[C:58]([F:60])[CH:59]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11](C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[N:10]=[C:9]2[NH:34][C:35](=[O:56])[C:36]1[CH:41]=[C:40]([C:42]([N:44]2[CH2:48][CH2:47][CH2:46][C@H:45]2[CH2:49][N:50]2[CH2:54][CH2:53][CH2:52][CH2:51]2)=[O:43])[CH:39]=[CH:38][C:37]=1[F:55].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:57]=[C:58]([F:60])[CH:59]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[NH:34][C:35](=[O:56])[C:36]1[CH:41]=[C:40]([C:42]([N:44]2[CH2:48][CH2:47][CH2:46][C@H:45]2[CH2:49][N:50]2[CH2:54][CH2:53][CH2:52][CH2:51]2)=[O:43])[CH:39]=[CH:38][C:37]=1[F:55]
Reactant: O=C(Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc(Cc3cc(F)cc(F)c3)cc12)c1cc(C(=O)N2CCC[C@H]2CN2CCCC2)ccc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1n[nH]c2ccc(Cc3cc(F)cc(F)c3)cc12)c1cc(C(=O)N2CCC[C@H]2CN2CCCC2)ccc1F
Reaction time: 2 h
Yield: 66.8 %

Procedure:
N-[5-(3,5-Difluoro-benzyl)-1-trityl-1H-indazol-3-yl]-2-fluoro-5-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-benzamide (90 mg, 0.112 mmol) in DCM (1 mL) was treated with TFA (0.17 mL, 2.24 mmol). After two hours at room temperature, DCM was added (25 mL) and the organic phase was washed with aqueous NaHCO3, water and brine. Drying over sodium sulphate, evaporation and purification of the crude over silica gel (eluent: DCM, MeOH, 7N NH3 in MeOH 9:1:0.1) afforded 42 mg of title compound.
Reaction SMILES: NC1(C2C=CC(C3C(C4C=CC=CC=4)=CC4C(=O)CCCC=4N=3)=CC=2)CCC1.C(OC(=O)[NH:35][C:36]1([C:40]2[CH:45]=[CH:44][C:43]([C:46]3[C:55]([C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)=[CH:54][C:53]4[CH2:52][N:51]([CH2:62][CH3:63])[CH2:50][CH2:49][C:48]=4[N:47]=3)=[CH:42][CH:41]=2)[CH2:39][CH2:38][CH2:37]1)(C)(C)C>>[CH2:62]([N:51]1[CH2:50][CH2:49][C:48]2[N:47]=[C:46]([C:43]3[CH:44]=[CH:45][C:40]([C:36]4([NH2:35])[CH2:37][CH2:38][CH2:39]4)=[CH:41][CH:42]=3)[C:55]([C:56]3[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=3)=[CH:54][C:53]=2[CH2:52]1)[CH3:63]
Reactant: CCN1CCc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2C1
Agent: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)C(=O)CCC4)cc2)CCC1
Product: CCN1CCc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cc2C1
Yield: 156.4 %

Procedure:
Following the procedure for 2-(4-(1-aminocyclobutyl)phenyl)-3-phenyl-7,8-dihydroquinolin-5(6H)-one, tert-butyl(1-(4-(6-ethyl-3-phenyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)phenyl)cyclobutyl)carbamate (14 mg, 0.03 mmol) was reacted to afford the title compound (18 mg, quantitative). LCMS (Method A): RT=0.44 min, M-NH2=367. 1H NMR (500 MHz, MeOD) 7.76 (1H, s), 7.45 (2H, d), 7.42 (2H, d), 7.30-7.29 (3H, m), 7.19-7.18 (2H, m), 3.47 (2H, q), 3.46 (2H, t), 3.39 (2H, br s), 3.32 (2H, m), 2.77-2.71 (2H, m), 2.60-2.54 (2H, m), 2.27-2.18 (1H, m), 1.99-1.90 (1H, m), 1.50 (3H, t).
Reaction SMILES: [OH:1][NH:2][C:3](=[O:27])[CH:4]=[CH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=1)(=[O:17])=[O:16])[CH:10]=[CH:9]2.[Cl-].[NH4+]>C(O)(C)C.O.[Fe]>[NH2:24][C:21]1[CH:20]=[CH:19][C:18]([S:15]([N:11]2[C:12]3[C:8](=[CH:7][C:6]([CH:5]=[CH:4][C:3]([NH:2][OH:1])=[O:27])=[CH:14][CH:13]=3)[CH:9]=[CH:10]2)(=[O:17])=[O:16])=[CH:23][CH:22]=1
Reactant: O=C(C=Cc1ccc2c(ccn2S(=O)(=O)c2ccc([N+](=O)[O-])cc2)c1)NO
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CC(C)O
Product: Nc1ccc(S(=O)(=O)n2ccc3cc(C=CC(=O)NO)ccc32)cc1
Yield: 64.6 %

Procedure:
Compound 7 was synthesized via the route shown in Scheme 2 in Example 3. A suspension of Compound 6 (0.10 g, 0.26 mmol), iron powder (0.05 g, 0.77 mmol) and ammonium chloride (0.03 g, 0.52 mmol) in isopropyl alcohol (5 ml) and water (1 ml) was refluxed for 4 h. After the reaction mixture was concentrated under reduced pressure, it was quenched with water and extracted with CH2Cl2. The combined organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The reaction mixture was purified by silica gel chromatography (CH2Cl2:CH3OH=10:1:1% NH3(aq)) to afford Compound 7 (0.06 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[N:10]=[C:4]2[CH:3]=1.[C:17](=[O:24])([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[NH2:18].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[O:14]1[CH2:15][CH2:16][N:11]([C:9]2[N:10]=[C:4]3[CH:3]=[C:2]([NH:18][C:17](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:7]=[CH:6][N:5]3[N:8]=2)[CH2:12][CH2:13]1
Reactant: Brc1ccn2nc(N3CCOCC3)nc2c1
Reactant: CC(C)(C)OC(N)=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1ccn2nc(N3CCOCC3)nc2c1
Temperature: 110 °C
Yield: 101.1 %

Procedure:
To an argon purged solution of 4-(7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)morpholine (321 mg, 1.13 mmol) in dioxane (8 ml) are added tert-butyl carbamate (159 mg, 1.36 mmol), tris(dibenzylideneacetone)dipalladium(0) (20.8 mg, 22.7 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (26.2 mg, 45.4 μmol) and cesium carbonate (517 mg, 1.59 mmol). The reaction vessel is sealed and heated to 110° C. for 20 hours. The crude material is applied on silica and purified by flash chromatography on a 20 g silica column using heptane/ethyl acetate 10-70% as eluent affording tert-butyl 2-morpholino-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamate (365 mg, 101%) as a light yellow solid. mp.: 92-3° C. MS: m/z=320.1 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]([CH3:15])[CH:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:8]([OH:10])=O)=[O:5])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.[CH3:31][NH:32][C:33](=[O:45])[C@H:34]([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1)[NH2:35].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:31][NH:32][C:33](=[O:45])[C@H:34]([CH2:36][C:37]1[CH:38]=[CH:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=1)[NH:35][C:8](=[O:10])[CH:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH3:15]
Reactant: CNC(=O)[C@@H](N)Cc1ccc(OC)cc1
Reactant: CCOC(=O)C(C)C(CC(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C(C)C(CC(C)C)C(=O)N[C@@H](Cc1ccc(OC)cc1)C(=O)NC
Temperature: 0 °C

Procedure:
A mixture of 3-(ethoxycarbonyl)-2-(2-methylpropyl)butanoic acid (7.5 g., 0.037 mol.) and dichloromethane (70 mls.) was stirred and cooled to 0° C. To the mixture was added dropwise a solution of N,N'-dicyclohexylcarbodiimide (7.6 g., 0.37 mol.) in dichloromethane (20 mls.) and the reaction mixture was allowed to warm to room temperature. A solution of O-methyl-L-tyrosine N-methylamide (7.7 g., 0.037 mol.) in dichloromethane (45 mls.) was added to the reaction mixture and the resulting mixture was stirred overnight at room temperature. A saturated sodium bicarbonate solution (100 mls.) was added to the reaction mixture and the resulting mixture was stirred for an additional hour. The reaction mixture was filtered and the organic layer recovered and then dried over anhydrous sodium sulfate. The solvent was removed by evaporation in vacuo to yield a sticky brown solid. Th solid was purified by chromatography on normal phase silica eluting with 20% hexane in ethyl acetate to yield N-[3-(ethoxycarbonyl)-2-(2-methylpropyl)butanoyl]-O-methyl-L-tyrosine N-methylamide as a mixture of 4 diastereomers.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].N1C=CC=CC=1.[F:12][C:13]([F:24])([F:23])[C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][N:15]=1>C(Cl)Cl>[CH3:5][O:4][N:3]([CH3:2])[C:18](=[O:19])[C:17]1[CH:21]=[CH:22][C:14]([C:13]([F:24])([F:23])[F:12])=[N:15][CH:16]=1
Reactant: CNOC
Reactant: O=C(Cl)c1ccc(C(F)(F)F)nc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CON(C)C(=O)c1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of N,O-dimethylhydroxylamine hydrochloride (9.47 g, 97.1 mmol) and pyridine (18.6 mL, 230 mmol) in CH2Cl2 (100 mL) was added a solution of 6-(trifluoromethyl)nicotinoyl chloride (18.50 g, 88.28 mmol) in CH2Cl2 (250 mL) over 3-5 min. The reaction mixture was stirred at rt overnight, and then carefully quenched with 150 mL of saturated aq. NaHCO3 solution and stirred for about 1 hr. The mixture was diluted with CH2Cl2 (50 mL) and the organic phase was separated and washed with aq. NaHCO3 solution (100 mL) and brine (50 mL), dried (Na2SO4), filtered, and evaporated. The residue was redissolved in toluene (about 50 mL) and evaporated again to azeotrope the pyridine off. This was repeated with toluene (about 50 mL). The product was isolated as a colorless oil (with a small amount of crystalline material) (19.1 g, 92%).
Reaction SMILES: Br[CH:2]1[CH2:7][O:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]1=O.Cl.[C:12]([C:15]1[C:16]([CH3:26])=[CH:17][C:18]([CH3:25])=[C:19]([CH:24]=1)[C:20]([O:22][CH3:23])=[O:21])(=[NH:14])[NH2:13].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:8][C:4]1([CH3:9])[C:3]2[N:14]=[C:12]([C:15]3[C:16]([CH3:26])=[CH:17][C:18]([CH3:25])=[C:19]([CH:24]=3)[C:20]([O:22][CH3:23])=[O:21])[NH:13][C:2]=2[CH2:7][O:6][CH2:5]1
Reactant: CC1(C)COCC(Br)C1=O
Reactant: COC(=O)c1cc(C(=N)N)c(C)cc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(-c2nc3c([nH]2)COCC3(C)C)c(C)cc1C
Temperature: 100 °C
Yield: 15.6 %

Procedure:
A mixture of 5-bromo-3,3-dimethyldihydro-2H-pyran-4(3H)-one (compound 449.2, 150 mg, 0.72 mmol), methyl 5-carbamimidoyl-2,4-dimethylbenzoate hydrochloride (compound 2.5, 135 mg, 0.55 mmol), and potassium carbonate (228 mg, 1.65 mmol) in acetonitrile (8 mL) was heated at 100° C. for 48 hrs. The mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (10 mL) and washed with brine (20 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (50% ethyl acetate in hexanes) to yield the title compound as a white solid (27 mg, 15%).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH2:13][N:14]([CH:21]1[CH2:26][CH2:25][C:24](=[O:27])[NH:23][C:22]1=[O:28])[C:15]2=[O:20].Cl.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1>C1COCC1>[O:28]=[C:22]1[CH:21]([N:14]2[CH2:13][C:12]3[C:16](=[CH:17][CH:18]=[CH:19][C:11]=3[CH2:10][NH:9][C:30](=[O:37])[C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)[C:15]2=[O:20])[CH2:26][CH2:25][C:24](=[O:27])[NH:23]1
Reactant: O=C(Cl)c1ccncc1
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1CCC(N2Cc3c(CNC(=O)c4ccncc4)cccc3C2=O)C(=O)N1
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 62.9 %

Procedure:
Triethylamine (0.7 g, 7.4 mmol) was added to a stirred suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.7 g, 2.1 mmol) and isonicotinoyl chloride hydrochloride (0.5 g, 2.5 mmol) in THF (30 mL) at 5-10° C. After stirring for 10 minutes at 5° C., the mixture was stirred at room temperature overnight. The mixture was filtered, and the solid was slurried with hot methanol (30 mL) to give N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-isonicotinamide (0.5 g, 63%): mp 282-284° C.; 1H NMR (DMSO-d6) δ 2.01-2.06 (m, 1H), 2.38-2.66 (m, 2H), 2.86-2.98 (m, 1H), 4.41-4.64 (m, 4H, 2CH2), 5.12-5.19 (dd, J=4.6 and 13.0 Hz, 1H, CH), 7.48-7.67 (m, 3H, Ar), 7.78-7.80 (d, J=4.8 Hz, 2H, Ar), 8.73-8.75 (m, d, J=4.8 Hz, 2H, Ar), 9.39 (s, 1H, NH), 11.03 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.59, 31.18, 39.67, 46.27, 51.61, 121.25, 121.83, 128.38, 130.76, 131.68, 134.11, 140.24, 140.98, 150.27, 164.87, 168.03, 171.00, 172.84; Anal. calcd. for C20H18N4O4: C, 63.49; H, 4.79; N, 14.81. Found: C, 63.22; H, 4.73; N, 14.62.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([OH:3])=[O:2].Cl.[CH3:15]O>>[CH3:15][O:2][C:1](=[O:3])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc(S(N)(=O)=O)cc1

Procedure:
A slurry of 30.2 g (0.15 mole) of p-carboxybenzenesulfonamide in 500 ml of methanol was treated with 30 g of anhydrous hydrogen chloride and the mixture was heated at reflux temperature for 3 hr. The solution was concentrated under vacuum to give 32.3 g of white, crystalline residue. A 5.0 g portion of this residue was recrystallized from 25 ml of methanol to give 3.3 g of title compound as a white powder, mp 174°-178° C.
Reaction SMILES: F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.[F-].[Cs+].[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1B(O)O.[F:32][C:33]1[C:38]([CH2:39][O:40][C:41]2[CH:49]=[CH:48][C:47]3[C@@H:46]4[C@@H:50]([C:51]([O:53][CH2:54][CH3:55])=[O:52])[C@@H:45]4[CH2:44][C:43]=3[CH:42]=2)=[C:37]([CH3:56])[C:36](I)=[CH:35][CH:34]=1>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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[C:36]1[CH:35]=[CH:34][C:33]([F:32])=[C:38]([CH2:39][O:40][C:41]2[CH:49]=[CH:48][C:47]3[C@@H:46]4[C@@H:50]([C:51]([O:53][CH2:54][CH3:55])=[O:52])[C@@H:45]4[CH2:44][C:43]=3[CH:42]=2)[C:37]=1[CH3:56]
Reactant: CCOC(=O)[C@H]1[C@@H]2Cc3cc(OCc4c(F)ccc(I)c4C)ccc3[C@@H]21
Reactant: OB(O)c1c(Cl)cccc1Cl
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Product: CCOC(=O)[C@H]1[C@@H]2Cc3cc(OCc4c(F)ccc(-c5c(Cl)cccc5Cl)c4C)ccc3[C@@H]21
Temperature: 70 °C
Reaction time: 16 h

Procedure:
To a two-neck round bottom flask with a magnetic stirring bar, was added tris(dibenzylideneacetone)dipalladium(0) (29.5 mg, 0.032 mmol), tri-t-butylphosphonium tetrafluoroborate (18.6 mg, 0.064 mmol), cesium fluoride (652 g, 4.29 mmol), 2,6-dichlorophenylboronic acid (409 mg, 2.15 mmol), and the product of Step E (500 mg, 1.07 mmol). One neck of the flask was connected to a vacuum line while another neck was fitted with an argon balloon. The flask was then purged 8-10 times with argon. The vacuum line was replaced with a septum and anhydrous THF (10 mL) was added by syringe. The mixture was stirred in a 70° C. oil bath for 16 h. The reaction solution was filtrated and concentrated. The residue was carried on to hydrolysis at the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2)=[O:10])=[N:4][C:5](Br)=[CH:6][N:7]=1.[OH:25][CH2:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[C:3]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2)=[O:10])=[N:4][C:5]([C:31]2[CH:30]=[CH:29][CH:28]=[C:27]([CH2:26][OH:25])[CH:32]=2)=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)c2nc(Br)cnc2N)C1
Reactant: OCc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)c2nc(-c3cccc(CO)c3)cnc2N)C1
Temperature: 90 °C
Reaction time: 12 h
Yield: 93.7 %

Procedure:
1,1-dimethylethyl (3S)-3-{[(3-amino-6-bromopyrazin-2-yl)carbonyl]amino}piperidine-1-carboxylate (765.0 mg, 1.91 mmol) was dissolved in DMF followed by addition of 3-hydroxymethyl phenylboronic acid (349.0 mg, 2.23 mmol), K2CO3 (660.0 mg, 4.77 mmol) and Pd(PPh3)4 (10 mol %, 220 mg). This mixture was stirred at 90° C. under nitrogen for 12 hours. The reaction mixture was poured into water (150 mL), and extracted with ethyl acetate (3×50 mL). The organic layers were washed with brine (50 mL) then dried over anhydrous sodium sulfate. Filteration, concentration and column chromatography on silica (50% ethylacetate/hexanes) gave a solid which was dried to affored 765.0 mg (92% yield) of 1,1-dimethylethyl (3S)-3-[({3-amino-6-[3-(hydroxymethyl)phenyl]pyrazin-2yl}carbonyl)amino]piperidine-1-carboxylate: MS (EI) for C22H29N5O4: 428.23 (MH+).
Reaction SMILES: [CH2:1]([OH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[H-].[Na+].Cl[C:12]1[CH:22]=[CH:21][C:15]([C:16]([O:18]CC)=[O:17])=[CH:14][N:13]=1.[OH-].[Li+]>C1COCC1.CC(=O)OCC.C(O)(=O)C>[CH2:1]([O:8][C:12]1[CH:22]=[CH:21][C:15]([C:16]([OH:18])=[O:17])=[CH:14][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCO
Reactant: CCOC(=O)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Li+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCCOc1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.2 %

Procedure:
To a stirring solution of heptan-1-ol (0.84 ml, 5.93 mmol) in THF (10 mL) at 0° C. was added sodium hydride (0.25 g, 6.20 mmol, 60 wt % suspension in mineral oil). The reaction mixture was allowed to warm to room temperature. After 1 h, a solution of ethyl 6-chloronicotinate (1.00 g, 5.39 mmol) in THF (5 mL) was added and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with EA (50 mL) and washed with brine (100 mL). The organics were dried over MgSO4 and evaporated to dryness. The residue was diluted with THF (5 mL) and MeOH (2 mL) then 1 N lithium hydroxide (1.08 mL, 1.08 mmol) was added. The reaction mixture was stirred for 18 h. The reaction mixture was acidified by the addition of acetic acid (to pH 5) and the solvents were removed under vacuum. The product was extracted into EA (30 mL) and washed with water (100 mL). The organics were pre-absorbed onto silica gel and purified by chromatography (EA/isohexanes) to afford 131 mg (10%) of 6-(heptyloxy)nicotinic acid INT-11 as a white powder. LCMS-ESI (m/z) calculated for C13H19NO3: 237; found 238 [M+H]+, tR=2.52 min (Method 10).
Reaction SMILES: [Br:1][C:2]([Br:14])=[CH:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]([O:12]C)=[O:11])[CH2:6][CH2:5]1.[OH-].[K+]>CO>[Br:1][C:2]([Br:14])=[CH:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]([OH:12])=[O:11])[CH2:6][CH2:5]1
Reactant: COC(=O)[C@H]1CC[C@H](C=C(Br)Br)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)[C@H]1CC[C@H](C=C(Br)Br)CC1

Procedure:
trans-Methyl 4-(2,2-dibromovinyl)cyclohexanecarboxylate (4.2 g) was stirred in a solution of potassium hydroxide (1.09 g) in methanol (50 ml) overnight. The solvent was then removed under reduced pressure. Water (50 ml) was added and the mixture extracted with diethyl ether. The aqueous layer was then acidified with hydrochloric acid. Re-extraction with ether was followed by washing of the organic layer with brine and drying over anhydrous magnesium sulphate. Evaporation gave trans-4-(2,2-dibromovinyl)cyclohexanecarboxylic acid (3.6 g) as a pale yellow oil.