Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([CH3:12])=[N:4][C:5]([O:10][CH3:11])=[C:6]([CH2:8][CH3:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[NH:19]1[CH:23]=[CH:22][CH:21]=[N:20]1>O.[Cu](I)I>[CH2:8]([C:6]1[C:5]([O:10][CH3:11])=[N:4][C:3]([CH3:12])=[C:2]([N:19]2[CH:23]=[CH:22][CH:21]=[N:20]2)[CH:7]=1)[CH3:9]
Reactant: CCc1cc(Br)c(C)nc1OC
Reactant: c1cn[nH]c1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCc1cc(-n2cccn2)c(C)nc1OC
Temperature: 160 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
Into each of 2 microwave vials is added 3-bromo-5-ethyl-6-methoxy-2-methylpyridine (200 mg, 0.869 mmol), potassium carbonate (180 mg, 1.30 mmol), copper iodide (16 mg, 0.084 mmol) and pyrazole (59 mg, 0.869 mmol). The vials are flushed with N2 before anhydrous dimethylformamide (5.5 mL) is added and then sealed. The first reaction is heated in the CEM Discover microwave at 160° C. for 20 minutes. LC/MS shows the reaction is incomplete. The reaction is re-microwaved to 180° C. for 20 min and LC/MS suggests that the reaction is approximately 50% complete. The reaction is re-microwaved at 185° C. for 20 min then 185° C. for 30 min and LC/MS shows the reaction is largely complete. Reaction 2 is heated in the microwave to 185° C. for 1.5 hr and LC/MS shows the reaction is almost complete. The 2 reactions are combined and diluted with water and extracted with 3 portions of dichloromethane. The combined organic layers are washed with 2 portions of aqueous sodium hydroxide (1M), then dried over magnesium sulfate and evaporated to give a dark oil. The crude product is purified by flash chromatography on a 5-gram silica gel cartridge by elution with dichloromethane. Fractions containing the product are combined and the solvent evaporated. The residue is further purified by flash chromatography on a 5-gram silica gel cartridge by elution with heptane:ethyl acetate (19:1) then dichloromethane:heptane (1:1, increasing to 1:0). Clean fractions containing the product are combined and evaporated to give 3-ethyl-2-methoxy-6-methyl-5-(pyrazol-1-yl)pyridine as a yellow oil (102 mg, 27% yield). MS: m/e=218 (M+H); NMR (CDCl3): 7.70 (1H, d), 7.53 (1H, d), 7.37 (1H, s), 6.44 (1H, t), 3.99 (3H, s), 2.59 (2H, q), 2.29 (3H, s), 1.10 (3H, t)
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=O)[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O.C(OCC)(=O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([NH:21][CH:22]2[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH2:27]2)=[O:20])[N:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCCCCc1cn(Cc2ccccc2)nn1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)CCCCCc2cn(Cc3ccccc3)nn2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
6-(1-Benzyl-1H-1,2,3-triazol-4-yl)hexanoic acid (100 mg, 0.366 mmol), tert-butyl 4-aminopiperidine-1-carboxylate (81 mg, 0.402 mmol), HATU (278 mg, 0.732 mmol) and triethylamine (153 μl, 1.098 mmol) were dissolved in DMF (1220 μl) to give an orange solution. The reaction mixture was stirred at RT for 72 hrs, then concentrated under reduced pressure to yield a slurry. This was diluted with water and ethyl acetate. The organics were separated and washed with water, then concentrated under reduced pressure to yield the title compound.
Reaction SMILES: O[C@H]1CC[C@H]2[C@H]3[C@H](CC[C@]12C)[C@]1(C=O)C(=CCCC1)CC3.C[C@@H:23]1[C@@:40]2([CH:41]=[O:42])[C:27]([CH2:28][CH2:29][C@@H:30]3[C@@H:39]2[CH2:38][CH2:37][C@@:35]2([CH3:36])[C@H:31]3[CH2:32][CH2:33][C@@H:34]2[O:43][Si:44]([CH3:47])([CH3:46])[CH3:45])=[CH:26][CH2:25][CH2:24]1>>[CH3:46][Si:44]([CH3:45])([CH3:47])[O:43][C@H:34]1[CH2:33][CH2:32][C@H:31]2[C@H:30]3[C@H:39]([CH2:38][CH2:37][C@:35]12[CH3:36])[C@:40]1([CH:41]=[O:42])[C:27](=[CH:26][CH2:25][CH2:24][CH2:23]1)[CH2:28][CH2:29]3
Reactant: C[C@H]1CCC=C2CC[C@H]3[C@@H]4CC[C@H](O[Si](C)(C)C)[C@@]4(C)CC[C@@H]3[C@]21C=O
Agent: C[C@]12CC[C@H]3[C@@H](CCC4=CCCC[C@@]43C=O)[C@@H]1CC[C@@H]2O
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CCCC[C@@]43C=O)[C@@H]1CC[C@@H]2O[Si](C)(C)C

Procedure:
Substituting 17β-hydroxy-4-androsten-19-one for the 17β-hydroxy-1α-methyl-4-androsten-19-one above results in the formation of 17β-trimethylsiloxy-4-androsten-19-one.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH2:41])[C:5]2[N:6]=[CH:7][N:8]([C:39]=2[N:40]=1)[C@@H:9]1[O:38][C@H:28]([CH2:29][O:30][Si](CC)(CC)CC)[C@@H:19]([O:20][Si](CC)(CC)CC)[C@H:10]1[O:11][Si](CC)(CC)CC.[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([CH2:49][CH2:50][OH:51])=[CH:45][CH:44]=1>>[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([CH2:49][CH2:50][O:51][C:2]2[N:3]=[C:4]([NH2:41])[C:5]3[N:6]=[CH:7][N:8]([C:39]=3[N:40]=2)[C@@H:9]2[O:38][C@H:28]([CH2:29][OH:30])[C@@H:19]([OH:20])[C@H:10]2[OH:11])=[CH:45][CH:44]=1
Reactant: CC[Si](CC)(CC)OC[C@H]1O[C@@H](n2cnc3c(N)nc(Cl)nc32)[C@H](O[Si](CC)(CC)CC)[C@@H]1O[Si](CC)(CC)CC
Reactant: OCCc1ccc(Cl)cc1
Product: Nc1nc(OCCc2ccc(Cl)cc2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 50 °C

Procedure:
To a 250-mL, three-neck round bottom flask was added 2-chloro-2′,3′,5′-tri-O-(triethylsilyl)adenosine (5.0 g, 7.8 mmol, Example 4) and 2-(4-chlorophenyl)ethanol (15 mL). The mixture was flushed with nitrogen for 5–10 minutes, then heated to 50° C. To this mixture was added sodium hydride (1.56 g, 39 mmol, as a 60% dispersion in mineral oil) at such a rate as to avoid excessive gas evolution. The reaction was maintained at 50° C. for 20 hours, at which time HPLC indicated complete conversion to the fully deprotected, alkylated product. The reaction was then cooled to room temperature, carefully quenched with water (40 mL), and extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine (120 mL), dried (MgSO4), filtered, and concentrated under reduced pressure to afford a clear oil. This material was purified by passing through a plug of silica gel, eluting with CH2Cl2, 3% methanol in CH2Cl2, and 10% methanol in CH2Cl2. Those fractions containing products were combined and evaporated to dryness, affording the desired product as a white solid. 680 mg (21%).m.p.: 114–120° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:26])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)[O:11][C:6]=2[C:5]([F:27])=[C:4]([CH3:28])[C:3]=1[F:29].[H-].[Na+].Br[CH2:33][CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37]>>[F:29][C:3]1[C:4]([CH3:28])=[C:5]([F:27])[C:6]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)=[CH:9][C:8](=[O:26])[C:7]=2[C:2]=1[NH:1][CH2:33][CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37]
Reactant: CC(C)CCCBr
Reactant: Cc1c(F)c(N)c2c(=O)cc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)oc2c1F
Agent: [H-]
Agent: [Na+]
Product: Cc1c(F)c(NCCCC(C)C)c2c(=O)cc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)oc2c1F
Yield: 57.9 %

Procedure:
Substantially the same manner as that in Example 114 (1) was repeated except that 1.02 g (2.54 mmol) of 5-amino-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-7-methyl-4H-1-benzopyran-4-one obtained in Example 107 (1), 306 mg (7.65 mmol) of sodium hydride (60% oil dispersion) and 0.90 mL (6.3 mmol) of 1-bromo-4-methylpentane were used under argon atmosphere, to give 718 mg of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-7-methyl-5-(4-methylpentylamino)-4H-1-benzopyran-4-one (yield: 58%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([CH:11]=[O:12])=[N:9][N:8]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[C:5]2=[N:6][CH:7]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:27][C:28]1[CH:33]=[CH:32][N:31]=[CH:30][C:29]=1B(O)O>CN(C=O)C.O.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>[CH3:27][C:28]1[CH:33]=[CH:32][N:31]=[CH:30][C:29]=1[C:2]1[CH:3]=[C:4]2[C:10]([CH:11]=[O:12])=[N:9][N:8]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccncc1B(O)O
Reactant: O=Cc1nn(C2CCCCO2)c2ncc(Br)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccncc1-c1cnc2c(c1)c(C=O)nn2C1CCCCO1
Temperature: 90 °C

Procedure:
To a heterogeneous solution of 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbaldehyde (XI) (0.21 g, 0.67 mmol) and K3PO4 (0.212 g, 1 mmol) in DMF (5 mL) and water (0.5 mL) was added 4-methyl-pyridine-3-boronic acid (LVI) (0.101 g, 0.74 mmol). The solution was purged with nitrogen by using nitrogen/vacuum cycle (3×). Pd(PPh3)4 (23 mg, 0.02 mmol) was added to the solution and again purged with nitrogen. The solution was heated at 90° C. for 4 h under nitrogen. The solution was filtered through a pad of Celite while it was still hot. The Celite was washed with DCM (3×). The combined filtrate was concentrated under vacuum. The residue was dissolved in DCM, and washed subsequently with saturated NaHCO3 solution and brine. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to produce 5-(4-methylpyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbaldehyde (LVII). The crude product was used directly for step 2 without further purification. ESIMS found for C18H18N4O2 m/z 323.4 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([CH2:6][C:7]([CH3:13])([CH3:12])[CH2:8]2)=[C:4]([CH3:14])[C:3]=1[CH:15]=O.O.[OH-].[Na+].Cl.[CH3:21][C:22]([CH3:24])=[O:23]>>[Cl:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([CH2:6][C:7]([CH3:12])([CH3:13])[CH2:8]2)=[C:4]([CH3:14])[C:3]=1[CH:15]=[CH:21][C:22](=[O:23])[CH3:24]
Reactant: Cc1c(Cl)c(C=O)c(C)c2c1CC(C)(C)C2
Reactant: CC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)C=Cc1c(C)c2c(c(C)c1Cl)CC(C)(C)C2
Yield: 65 %

Procedure:
To a solution of 21.8 g of the 6-chloro-2,2,4,7-tetramethylindan-5-carboxaldehyde in 67 ml of absolute acetone was added 33 ml of water and 36.5 g of 2% NaOH. After refluxing for 20 hours, the solution was acidified with 2N HCl and extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography to afford 16.6 g of the title compound as yellow solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]2[C:7]([I:15])=[N:6]1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(N(CC)CC)C>CN(C)C=O>[I:15][C:7]1[C:8]2[C:9](=[N:10][CH:11]=[N:12][C:13]=2[NH2:14])[N:5]([CH2:4][CH2:3][CH2:2][N:20]2[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]2)[N:6]=1
Reactant: CN1CCNCC1
Reactant: Nc1ncnc2c1c(I)nn2CCCBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1CCN(CCCn2nc(I)c3c(N)ncnc32)CC1
Temperature: 70 °C
Reaction time: 66.25 h
Yield: 45.3 %

Procedure:
A suspension of 1-(3-bromopropyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.500 g, 1.31 mmol) in dimethylformamide (10 mL) was treated with 1-methylpiperazine (0.157 g, 1.572 mmol) and triethylamine (0.133 g, 1.31 mmol). The reaction mixture was stirred at 70° C. for 66.25 h. Solvent was removed under reduced pressure. Dichloromethane (15 mL) and 1 N hydrochloric acid (20 mL) were added. The layers were partitioned and the aqueous layer was washed with dichloromethane (100 mL). The aqueous layer was neutralized to pH 13 and then extracted with dichloromethane (250 mL). The organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a step-wise gradient; 20% methanol in dichloromethane to 50% methanol in dichloromethane over 55 minutes on a 35 g ISCO column. The column afforded 0.238 g (45%) of pure 3-iodo-1-[3-(4-methylpiperazino)propyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine. 1H NMR (DMSO-d6, 400 MHz) δ 8.191 (s, 1H), 4.308-4.273 (t, 2H), 2.262-2.228 (m, 10H), 1.944-1.877(m, 2H); LCMS (Thermoquest AQA single-quad MS, Genesis C18 column, 3 μm particle size, 33×4.6 mm; 70% 50 mM ammonium acetate in water to 95% acetonitrile over 6 min, 0.8 to 0.5 mL/min) Rt 0.75 min (100%), MH+ 402.1.
Reaction SMILES: Cl.[CH:2]12[NH:10][CH:6]([CH2:7][CH2:8][CH2:9]1)[CH2:5][C:4](=O)[CH2:3]2.[C:12]1([NH:18]N)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1C2C(=CC=CC=2)C=C1.O.C(O)(=O)C(O)=O.C(O)(=O)C(O)=O>C(Cl)Cl>[NH:10]1[CH:2]2[C:3]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:18][C:4]=3[CH2:5][CH:6]1[CH2:7][CH2:8][CH2:9]2
Reactant: NNc1ccccc1
Reactant: O=C1CC2CCCC(C1)N2
Agent: Cl
Agent: O=C(O)C(=O)O
Agent: c1ccc2[nH]ccc2c1
Solvent: O
Solvent: ClCCl
Product: c1ccc2c3c([nH]c2c1)CC1CCCC3N1

Procedure:
This compound was prepared from 9-azabicyclo[3.3.1]nonan-3-one hydrochloride and phenylhydrazine by Fischer indole synthesis as described in Example 1, Method A, to give colorless crystals, mp 198°-203° C. (from methylene chloride; it was also converted to a hydrogen oxalate hemihydrate, mp 68°-72° C. (from ethanol-ether).
Reaction SMILES: C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.Br[C:48]1[CH:53]=[CH:52][CH:51]=[C:50]([N+:54]([O-:56])=[O:55])[CH:49]=1.Cl.Cl.[CH:59]([N:62]1[CH2:67][C@@H:66]2[CH2:68][C@H:63]1[CH2:64][NH:65]2)([CH3:61])[CH3:60].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:59]([N:62]1[CH2:67][C@@H:66]2[CH2:68][C@H:63]1[CH2:64][N:65]2[C:48]1[CH:53]=[CH:52][CH:51]=[C:50]([N+:54]([O-:56])=[O:55])[CH:49]=1)([CH3:61])[CH3:60]
Reactant: CC(C)N1C[C@@H]2C[C@H]1CN2
Reactant: O=[N+]([O-])c1cccc(Br)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)N1C[C@@H]2C[C@H]1CN2c1cccc([N+](=O)[O-])c1
Temperature: 40 °C
Yield: 78.4 %

Procedure:
A solution of BINAP (0.47 g, 0.75 mmol) and tris(dibenzylideneacetone)dipalladium (0) (0.34 g, 0.37 mmol) in toluene (120 mL) was heated to 90° C. during 15 minutes under nitrogen. The reaction mixture was cooled to 40° C. before adding 1-bromo-3-nitrobenzene (1.89 g, 9.37 mmol), (1S,4S)-2-isopropyl-2,5-diazabicyclo[2.2.1]heptane dihydrochloride (2.0 g, 9.37 mmol) and sodium tert-butoxide (3.14 g, 32.74 mmol). The reaction was heated to 90° C. during 18 hours under nitrogen. After return to room temperature, the reaction was diluted with ethyl acetate and filtered through celite. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with a mixture of DCM/7N NH3 in methanol (96/4) to afford the title compound (1.92 g, 78%).
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C:10]2[C:15]([NH2:16])=[N:14][CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:18]1[N:23]=[C:22]([NH:24][C@@H:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH3:26])[C:21]([NH2:33])=[N:20][CH:19]=1.[CH:34](O)=[O:35]>[Pd]>[C:1]1([C@H:7]([N:9]2[C:10]3=[N:11][CH:12]=[CH:13][N:14]=[C:15]3[NH:16][C:34]2=[O:35])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:27]1([C@H:25]([NH:24][C:22]2[C:21]([NH2:33])=[N:20][CH:19]=[CH:18][N:23]=2)[CH3:26])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: C[C@@H](Nc1nc(Br)cnc1N)c1ccccc1
Reactant: O=CO
Agent: [Pd]
Agent: C[C@@H](Nc1nccnc1N)c1ccccc1
Product: C[C@H](c1ccccc1)n1c(=O)[nH]c2nccnc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(R)-N2-(1-Phenylethyl)pyrazine-2,3-diamine. The title compound was prepared by dissolving (R)-6-bromo-N2-(1-phenylethyl)pyrazine-2,3-diamine (1.00 g, 3.37 mmol) in neat formic acid (15 mL), and adding 10% Pd/C (0.34 mmol). This solution was purged with hydrogen gas at 1 atm., and stirred for 4 hours at room temperature. Upon completion, the reaction was filtered through celite and concentrated. The crude material was purified using silica gel chromatography (0-10% methanol in dichloromethane). Clean fractions were combined and condensed to afford 0.65 g (3.03 mmol, 90%) of (R)-N2-(1-phenylethyl)pyrazine-2,3-diamine. MS (ESI) m/z 215.4 [M+1]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([OH:9])[C:6]([O:10][CH2:11][CH2:12][CH3:13])=[CH:5][N:4]=1.CO[CH:16]=[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([I:27])[CH:25]=2)[C:20](=[O:28])[NH:19][C:18]1=[O:29]>CN(C)C=O>[OH:9][C:7]1[C:6]([O:10][CH2:11][CH2:12][CH3:13])=[CH:5][N:4]=[C:3]([CH2:2][NH:1][CH:16]=[C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([I:27])[CH:25]=3)[C:20](=[O:28])[NH:19][C:18]2=[O:29])[CH:8]=1
Reactant: CCCOc1cnc(CN)cc1O
Reactant: COC=C1C(=O)NC(=O)c2ccc(I)cc21
Solvent: CN(C)C=O
Product: CCCOc1cnc(CNC=C2C(=O)NC(=O)c3ccc(I)cc32)cc1O

Procedure:
A mixture of 2-aminomethyl-5-propoxy-pyridin-4-ol (137 mg, 0.75 mmole) in 10 mL of N,N-dimethylformamide is stirred, then 4-methoxymethylene-6-iodo-4H-isoquinoline-1,3-dione (247 mg, 0.75 mmole) is added and the reaction mixture stirred for one hour. The reaction mixture is evaporated to dryness, triturated with 5% methanol in chlororform, filtered washed with fresh 5% methanol in chloroform, washed with acetonitrile and dried to give a pink solid, 313 mg, (87%); MS (ES+): m/z 479.9 (M+H).
Reaction SMILES: [Br:1][C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[CH2:10][C:11]1([C:24]([O:26]CC)=[O:25])[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.[OH-].[Li+]>CO>[Br:1][C:2]1[N:6]([CH:7]([CH3:8])[CH3:9])[N:5]=[CH:4][C:3]=1[CH2:10][C:11]1([C:24]([OH:26])=[O:25])[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:13][CH2:12]1
Reactant: CCOC(=O)C1(Cc2cnn(C(C)C)c2Br)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)n1ncc(CC2(C(=O)O)CCN(C(=O)OC(C)(C)C)CC2)c1Br
Temperature: 80 °C
Reaction time: 18 h
Yield: 74.3 %

Procedure:
To a solution of 1-tert-butyl 4-ethyl 4-((5-bromo-1-isopropyl-1H-pyrazol-4-yl)methyl)piperidine-1,4-dicarboxylate (14.5 g, 31.6 mmol) in methanol (50 mL) was added lithium hydroxide (1.52 g, 36.2 mmol) and the mixture was stirred at 80° C. for 18 hours. An additional portion of lithium hydroxide (2.55 g, 63.3 mmol) was added and the mixture was heated under vigorous reflux for 3 hours, cooled to room temperature, the solvent was removed in vacuo. The residue was washed with ethyl acetate, filtered, and the filtrate was saved. The solids were dissolved in 2 N aqueous sodium hydroxide (40 mL) and then acidified to pH 5 with 10% citric acid solution. The aqueous solution was extracted with ethyl acetate (3×40 mL), the organics were combined, dried over magnesium sulfate, filtered and then combined with the original filtrate. The solvent was removed from the filtrate under reduced pressure and the resulting residue was purified by flash column chromatography (ethyl acetate/heptanes) to afford 4-((5-bromo-1-isopropyl-1H-pyrazol-4-yl)methyl)-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (10.1 g, 74%) as a colorless solid. +ESI (M+H) 429.9; 1H NMR (300 MHz, CDCl3, δ): 7.41 (s, 1H), 4.64 (m, 1H), 3.94 (m, 2H), 2.95 (m, 2H), 2.68 (m, 2H), 2.09 (m, 2H), 1.47 (m, 17H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=O)=[C:24]([CH:28]=[CH2:29])[N:23]=[C:22]3[O:30][CH2:31][CH3:32])=[C:16]([F:33])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.Cl.[NH2:41][OH:42]>O>[C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[N:41][OH:42])=[C:24]([CH:28]=[CH2:29])[N:23]=[C:22]3[O:30][CH2:31][CH3:32])=[C:16]([F:33])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: C=Cc1nc(OCC)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2F)c1C=O
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: C=Cc1nc(OCC)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2F)c1C=NO
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.8 %

Procedure:
Intermediate (15b) (19.5 g, 43.4 mmol) was dissolved in pyridine (100 mL, 1 mol). Hydroxylamine hydrochloride (9.0 g, 130 mmol) was added, followed by water (50 mL, 3 mol), and the mixture was stirred at room temperature overnight. Water (100 mL) was then added and the mixture was stirred for 20 minutes. The precipitant was filtered off and dried to yield intermediate (15c) (13.5 g). MS m/z: [M+H+] calcd for C26H28FN3O4, 466.2; found 466.4. 1H-NMR (CDCl3): 9.78 (1H, s), 7.81 (1H, d), 7.48 (2H, m), 7.26 (1H, s), 7.0 (4H, m), 6.20 (1H, d), 5.53 (1H, d), 5.50 (2H, s), 4.55 (2H, q), 1.43 (3H, t), 1.25 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:23])([CH3:22])[C:9]([CH:11]([C:17]([O:19]CC)=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:10])=[C:4]([F:24])[CH:3]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>OS(O)(=O)=O.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[C:4]([F:24])[CH:3]=1)[C:8]([CH3:22])([CH3:23])[C:9](=[O:10])[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:17]2[OH:19]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)C(C)(C)c1ccc(Cl)cc1F
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(O)c2cc(Cl)cc(F)c2C(C)(C)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.3 %

Procedure:
To diethyl 2-(2-(4-chloro-2-fluorophenyl)-2-methylpropanoyl)malonate (2.20 g, 6.1 mmol), was added P2O5 (3.5 g, 25 mmol) in H2SO4 (3.3 mL) at 0° C. The reaction was then allowed to warm to ambient temperature and stirred for 1 hour. The reaction mixture was poured into ice, diluted with 100 mL of EtOAc, added to a separatory funnel, partitioned with water, washed 2 times with 75 mL of water, separated, dried over Na2SO4, and concentrated in vacuo to give the title compound (0.75 g) which was used without further purification. MS (m/z)=313 (M+H)+.
Reaction SMILES: [CH2:1]([S:3]([CH2:6][CH2:7][CH2:8][C:9]12[CH2:16][CH2:15][C:12]([C:17]([OH:19])=O)([CH2:13][CH2:14]1)[CH2:11][CH2:10]2)(=[O:5])=[O:4])[CH3:2].C(Cl)(=O)C(Cl)=O.[CH3:26][NH2:27]>C(Cl)Cl.CN(C=O)C>[CH2:1]([S:3]([CH2:6][CH2:7][CH2:8][C:9]12[CH2:16][CH2:15][C:12]([C:17]([NH:27][CH3:26])=[O:19])([CH2:13][CH2:14]1)[CH2:11][CH2:10]2)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)CCCC12CCC(C(=O)O)(CC1)CC2
Reactant: CN
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCS(=O)(=O)CCCC12CCC(C(=O)NC)(CC1)CC2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Carboxylic acid 11-8 (3.0 g, 11 mmol) was dissolved in 50 mL of anhydrous methylene chloride under nitrogen atmosphere, treated with oxalyl chloride (2 M in methylene chloride, 16.2 mL, 32.4 mmol) and subsequently with 5 drops of DMF. The reaction was stirred at room temperature under nitrogen atmosphere for 90 min, then evaporated and placed under vacuum for 20 min. The acid chloride was dissolved in anhydrous methylene chloride (12 mL), cooled in an ice-bath, and then treated dropwise with a solution of methylamine (2M in THF, 27 mL, 54 mmol). Upon addition of the methylamine, the cooling bath was removed and the reaction stirred at ambient temperature for 30 min. The mixture was diluted with 200 mL of methylene chloride and washed with 1N aqueous HCl, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was subjected to chromatography on silica gel eluting with a gradient from 0 to 3% methanol in ethyl acetate to give 4-[3-(ethylsulfonyl)propyl]-N-methylbicyclo[2.2.2]octane-1-carboxamide 11-9 as a white powder. MS (ESI+)=302 (M+1). 1H NMR (500 MHz, CDCl3): δ 5.56 (1H, br s), 3.02 (2H, q, J=7 Hz), 2.94 (2H, dd, J=7.5 Hz), 2.82 (3H, d, J=4 Hz), 1.80 (8H,m), 1.45 (9H, m), 1.28 (2H, m) ppm.