Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([C:6]1[CH:15]=[CH:14][C:13]2[CH2:12][CH:11]([C:16]([O:18]C)=[O:17])[CH2:10][CH2:9][C:8]=2[N:7]=1)([CH3:5])[CH3:4].[OH-].[Na+].OP(O)(O)=O>CO.O>[F:21][C:2]([F:1])([F:20])[C:3]([C:6]1[CH:15]=[CH:14][C:13]2[CH2:12][CH:11]([C:16]([OH:18])=[O:17])[CH2:10][CH2:9][C:8]=2[N:7]=1)([CH3:5])[CH3:4]
Reactant: COC(=O)C1CCc2nc(C(C)(C)C(F)(F)F)ccc2C1
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(c1ccc2c(n1)CCC(C(=O)O)C2)C(F)(F)F

Procedure:
A solution of methyl 2-(1,1,1-trifluoro-2-methylpropan-2-yl)-5,6,7,8-tetrahydroquinoline-6-carboxylate (0.97 g, 3.2 mmol) in methanol (20 mL) was treated with 1 M aqueous sodium hydroxide (6 mL, 2 equiv), and the mixture was heated to reflux. After 1.5 h the cooled mixture was diluted with water. (40 mL), adjusted to pH 6 with H3PO4, and extracted with DCM (3×20 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to a solid (0.76 g, 82%). 1H NMR (400 MHz, DMSO-d6) δ 12.34 (br s, 1H), 7.55 (d, J=8.1 Hz, 1H), 7.41 (d, J=8.1 Hz, 1H), 2.99-2.83 (m, 4H), 2.77-2.69 (m, 1H), 2.19-2.11 (m, 1H), 1.91-1.81 (m, 1H), 1.54 (s, 6H); m/z=288.4 (M+H)+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1[C:21]2[C:12](=[CH:13][CH:14]=[C:15]3[C:20]=2N=CC=C3)C=CC=1.[N+:22]1([O-:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O[Li])(C)(C)C>C(OCC)(=O)C.[Cu]I.CO.CN1C(=O)N(C)CCC1>[C:2]1([C:23]2[CH:24]=[CH:25][CH:26]=[C:27]([C:12]3[CH:21]=[CH:20][CH:15]=[CH:14][CH:13]=3)[N+:22]=2[O-:28])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1ccccc1
Reactant: [O-][n+]1ccccc1
Reactant: c1cnc2c(c1)ccc1cccnc12
Agent: [Cu]I
Agent: [Li]OC(C)(C)C
Solvent: CO
Solvent: CN1CCCN(C)C1=O
Solvent: CCOC(C)=O
Product: [O-][n+]1c(-c2ccccc2)cccc1-c1ccccc1
Yield: 202.2 %

Procedure:
Copper(I) iodide (19 mg, 0.1 mmol), iodobenzene (408 mg, 2.0 mmol), 1,10-phenanthroline (18 mg, 0.1 mmol), pyridine N-oxide (95 mg, 1.0 mmol), t-BuOLi (145 mg, 1.8 mmol), and anhydrous DMPU (0.5 mL), 125° C., 1 hour. After column chromatography (ethyl acetate, then 15% MeOH in ethyl acetate) 50 mg of 2,6-diphenylpyridine 1-oxide (20%) was obtained as an off-white solid. Additionally, 2-phenylpyridine 1-oxide (100 mg, 58%) was obtained as a colorless solid. These compounds are known.7,12 2-Phenylpyridine 1-oxide: Rf=0.46 (3/7 methanol/ethyl acetate). The molecule structure of 2-phenylpyridine 1-oxide and its 1H NMR spectrum are shown in FIG. 59. 1H NMR (300 MHz, CDCl3) δ 7.17-7.34 (m, 2H), 7.38-7.53 (m, 4H), 7.80 (dd, J=7.7 Hz, 1.7 Hz, 2H), 8.33 (d, J=6.0 Hz, 1H). 2,6-Diphenylpyridine 1-oxide: Rf=0.30 (1/1 ethyl acetate/hexanes). 1H NMR (300 MHz, CDCl3) δ 7.28-7.52 (m, 9H), 7.80-7.87 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[C:10]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH:11]=[CH:12][CH:13]=2)[N:5]=[C:4]([C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=3)[N:21]=2)[N:3]=1.CCN(CC)CC.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>C(Cl)Cl.O>[CH3:43][S:44]([N:17]1[CH2:16][CH2:15][N:14]([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([CH2:7][N:6]3[C:2]([CH3:1])=[N:3][C:4]([C:20]4[O:24][N:23]=[C:22]([C:25]5[CH:30]=[CH:29][C:28]([O:31][C:32]([F:33])([F:35])[F:34])=[CH:27][CH:26]=5)[N:21]=4)=[N:5]3)[CH:9]=2)[CH2:19][CH2:18]1)(=[O:46])=[O:45]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cccc(N2CCNCC2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cccc(N2CCN(S(C)(=O)=O)CC2)c1
Temperature: 25 °C

Procedure:
To a solution of 5-(5-methyl-1-(3-(piperazin-1-yl)benzyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole (Example 81; 110 mg, 0.23 mmol) and Et3N (70 mg, 0.69 mmol) in DCM (5 mL) at 0° C. was added methanesulfonyl chloride (34 mg, 0.30 mmol). The reaction mixture was allowed to warm to RT over 2 h, then diluted with H2O (10 mL) and extracted with EtOAc (2×10 mL). The combined organic layers were washed with H2O (10 mL) and brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure; the residue was purified by prep-HPLC (10% to 30% MeCN/H2O containing 0.1% trifluoroacetic acid) to give the title compound as an off-white solid; MS (ES+) C24H24F3N7O4S requires: 563. found: 564 [M+H]+; 1H-NMR (500 MHz, DMSO-d6) δ 8.22 (d, J=8.5 Hz, 2H), 7.61 (d, J=8.5 Hz, 2H), 7.24 (m, 1H), 6.96 (m, 2H), 6.70 (d, J=7.5 Hz, 1H), 5.49 (s, 2H), 3.98 (m, 4H), 3.25 (m, 4H), 2.92 (s, 3H), 2.58 (s, 3H).
Reaction SMILES: C([O:8][C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]([C:19]([O:21][CH3:22])=[O:20])=[C:11]([CH3:23])[N:10]=1)C1C=CC=CC=1.C1COCC1.[H][H]>[C].[Pd].C(O)C>[OH:8][C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]([C:19]([O:21][CH3:22])=[O:20])=[C:11]([CH3:23])[N:10]=1
Reactant: [H][H]
Reactant: COC(=O)c1cc(C(=O)OC)c(OCc2ccccc2)nc1C
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(=O)OC)c(O)nc1C
Yield: 48.2 %

Procedure:
A mixture of dimethyl 2-(benzyloxy)-6-methylpyridine-3,5-dicarboxylate (14.4 g), 10% palladium carbon (containing 55% water, 9.00 g), THF (20 mL), and ethanol (20 mL) was stirred at room temperature for 1 hour in a hydrogen atmosphere. The catalyst was filtered off, and then, the obtained filtrate was concentrated under reduced pressure. The obtained solid was washed with ethyl acetate to obtain the title compound (4.96 g).
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:37])[C:26]2[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([C:33]([F:36])([F:35])[F:34])[CH:27]=2)=[O:22])[CH2:17]1>>[F:32][C:30]1[CH:31]=[C:26]([CH:27]=[C:28]([C:33]([F:36])([F:34])[F:35])[CH:29]=1)[C:25]([NH:24][CH2:23][C:21](=[O:22])[NH:20][CH:18]1[CH2:19][N:16]([CH:5]2[CH2:6][CH2:7][C:2]([OH:1])([C:9]3[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=3)[CH2:3][CH2:4]2)[CH2:17]1)=[O:37]
Reactant: Cc1ccc(C2(O)CCC(=O)CC2)cn1
Reactant: O=C(CNC(=O)c1cc(F)cc(C(F)(F)F)c1)NC1CNC1
Product: Cc1ccc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cc(F)cc(C(F)(F)F)c4)C3)CC2)cn1

Procedure:
The title compounds were prepared as white solids from reductive amination of 4-hydroxy-4-(6-methyl-pyridin-3-yl)-cyclohexanone, as prepared in Example 13 Step B, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-5-fluoro-benzamide, as prepared in the previous step, using the procedure described in Step E of Example 1.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C@@H:15]([CH2:30][N:31]1[CH2:36][C:35](=[O:37])[N:34]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[CH3:44])[CH2:33][C:32]1([CH3:46])[CH3:45])[C@@H:16]([OH:29])[CH2:17][C@H:18]([C:21](=[O:28])[NH:22][CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:19][CH3:20])(C)(C)C.[C:48]([OH:55])(=[O:54])/[CH:49]=[CH:50]/[C:51]([OH:53])=[O:52].CC(C)(C)CNC(=O)[C@H](C)C[C@H](O)[C@@H](N)CN1CC(=O)N(C2C=CC=CC=2Cl)CC1(C)C>C(Cl)Cl.CO>[C:48]([OH:55])(=[O:54])/[CH:49]=[CH:50]/[C:51]([OH:53])=[O:52].[CH3:26][C:24]([CH3:25])([CH3:27])[CH2:23][NH:22][C:21](=[O:28])[C@H:18]([CH2:19][CH3:20])[CH2:17][C@H:16]([OH:29])[C@@H:15]([NH2:14])[CH2:30][N:31]1[CH2:36][C:35](=[O:37])[N:34]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[CH3:44])[CH2:33][C:32]1([CH3:45])[CH3:46].[NH2:14][C@@H:15]([CH2:30][N:31]1[CH2:36][C:35](=[O:37])[N:34]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[CH3:44])[CH2:33][C:32]1([CH3:45])[CH3:46])[C@@H:16]([OH:29])[CH2:17][C@@H:18]([CH2:19][CH3:20])[C:21]([NH:22][CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:28]
Reactant: CC[C@H](C[C@H](O)[C@H](CN1CC(=O)N(c2ccccc2C)CC1(C)C)NC(=O)OC(C)(C)C)C(=O)NCC(C)(C)C
Agent: C[C@H](C[C@H](O)[C@@H](N)CN1CC(=O)N(c2ccccc2Cl)CC1(C)C)C(=O)NCC(C)(C)C
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C[C@H](O)[C@@H](N)CN1CC(=O)N(c2ccccc2C)CC1(C)C)C(=O)NCC(C)(C)C
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
0.43 ml of trifluoroacetic acid (5.6 mmol) was added to a solution of 105 mg of {(1S,2S,4R)-4-(2,2-dimethylpropylcarbamoyl)-1-[2,2-dimethyl-4-(2-methylphenyl)-5-oxopiperazin-1-ylmethyl]-2-hydroxyhexyl}carbamic acid t-butyl ester obtained in Example (110c) (0.19 mmol) in methylene chloride (1.0 ml) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. After concentration under reduced pressure, a saturated sodium bicarbonate aqueous solution was added to the reaction mixture, followed by extraction with methylene chloride. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/methanol/triethylamine=9/1/0-90/10/1). 9.7 mg of fumaric acid (0.08 mmol) was added to a solution of 77 mg of (2R,4S,5S)-5-amino-6-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]-4-hydroxy-2-methylhexanoic acid (2,2-dimethylpropyl)amide obtained above (0.17 mmol) in methanol (2 ml), and the mixture was stirred at room temperature for five minutes. The reaction mixture was concentrated under reduced pressure, and n-hexane (1 ml) was added to the residue. The solid was collected by filtration to obtain 69 mg of the title compound (yield: 71%).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:7][Si:8]([CH3:11])([CH3:10])[CH3:9].[OH-].[Na+]>>[C:1]([NH:5][CH2:7][Si:8]([CH3:11])([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)CCl
Reactant: CC(C)(C)N
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)NC[Si](C)(C)C
Temperature: 200 °C

Procedure:
A mixture of tert-butylamine (18.0 mL, 171 mmol) and (chloromethyl)trimethylsilane (7.00 g, 57.1 mmol) was heated in a thick-walled glass tube at 200° C. overnight. After cooling to ambient temperature, the reaction mixture was poured into 1 N NaOH and extracted three times with diethyl ether. The combined organic extracts were washed with brine, dried (MgSO4), and the volatiles evaporated in vacuo. Distillation (atmospheric pressure; ˜135° C.) of the residual liquid gave the title compound 77 as a colorless liquid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=O)[NH:11][N:10]=2)[CH:2]=1.P(Cl)(Cl)([Cl:22])=O.Cl>C(#N)C.O1CCOCC1>[Cl:22][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([CH2:8][CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[N:10][N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]nc(CCc2cccnc2)c2ccccc12
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: Clc1nnc(CCc2cccnc2)c2ccccc12
Temperature: 60 °C
Reaction time: 3.5 h

Procedure:
Under exclusion of air, 2.4 g (9.55 mmol) 4-[2-(pyridin-3-yl)ethyl]phthalazin-1(2H)-one in 36 ml acetonitrile is mixed with 2.18 ml (23.8 mmol) phosphoryl chloride and 4.75 ml 4 N HCl in dioxane and stirred for 3.5 h at 60° C. After cooling to RT, the product is filtered off as hydrochloride and washed with CH3CN. The crystals are dissolved in about 10 ml H2O, mixed with 15 ml H2O and 1.5 ml sat. NH3 solution and extracted immediately 3 times with EtOAc. Drying (Na2SO4) of the organic phases and evaporation yield the title compound; FAB-MS (M+H)+=270.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=3)[CH:16]=2)[CH2:9]1)=O)(C)(C)C.[NH2:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1>>[NH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:28][CH2:29][CH2:30][C:31]4[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=4)[N:22]=3)[CH:18]=[CH:19][CH:20]=2)[CH2:9]1
Reactant: NCCc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC(Nc2cccc(-c3ccnc(Cl)n3)c2)C1
Product: Oc1ccc(CCNc2nccc(-c3cccc(NC4CCCNC4)c3)n2)cc1

Procedure:
Intermediate 8 was coupled with tyramine following procedure F and the resulting product deprotected by procedure G. LC-MS showed the product had the expected M+H+ of 390. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.2 (d, 1H) 6.95-7.6 (m, 8H) 6.7 (m, 2H) 4.95 (m, 1H) 3.7-3.9 (m, 2H) 3.5 (m, 1H) 2.8-3.2 (m, 5H) 1.6-2.4 (m, 5H).
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.O.O.O.C([O-])(=O)C.[Na+].[C:23]([O:27][CH2:28][CH3:29])(=[O:26])[CH:24]=[CH2:25].O>CN(C)C(=O)C>[F:12][C:11]([F:14])([F:13])[C:9]1[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=[C:2](/[CH:25]=[CH:24]/[C:23]([O:27][CH2:28][CH3:29])=[O:26])[N:7]2[CH:8]=1
Reactant: C=CC(=O)OCC
Reactant: FC(F)(F)c1cn2c(Br)cccc2n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)/C=C/c1cccc2nc(C(F)(F)F)cn12
Temperature: 110 °C
Reaction time: 24 h
Yield: 62.9 %

Procedure:
To a solution of 5-bromo-2-(trifluoromethyl)imidazo[1,2-a]pyridine (10.0 g, 37.7 mmol) in N,N-dimethylacetamide (60 mL) were added sodium acetate trihydrate (6.19 g, 75.0 mmol), ethyl acrylate (4.94 mL, 45.3 mmol) and [1,1′bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane complex (2.76 g, 3.77 mmol) at room temperature, and the mixture was stirred under nitrogen stream at 110° C. for 24 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80) to give the title compound (6.74 g, yield 63%).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][O:15][C:16]2[CH:29]=[CH:28][C:19]([CH:20]=[C:21]3[S:25][C:24](=[O:26])[NH:23][C:22]3=[O:27])=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)(=[O:5])=[O:4].C(OC(C1CC(C(OCC)=O)=C(C)NC=1C)=O)C>>[F:31][C:2]([F:1])([F:30])[S:3]([O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:20][CH:21]3[S:25][C:24](=[O:26])[NH:23][C:22]3=[O:27])=[CH:28][CH:29]=2)=[CH:11][CH:12]=1)(=[O:5])=[O:4]
Reactant: O=C1NC(=O)C(=Cc2ccc(OCCc3ccc(OS(=O)(=O)C(F)(F)F)cc3)cc2)S1
Agent: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Product: O=C1NC(=O)C(Cc2ccc(OCCc3ccc(OS(=O)(=O)C(F)(F)F)cc3)cc2)S1
Temperature: 180 °C
Yield: 38.3 %

Procedure:
2 g (4.22 mmole) 5-(4-[2-(4-trifluoromethanesulfonyloxyphenyl)ethoxy]benzylidene)thiazolidine-2,4-dione and 2.14 g (8.44 mmole) diethyl-1,4-dihydro-2,6-dimethyl-3.5-pyridine dicarboxylate were mixed and heated to 180° C. under vacuum when it melted, the temperature raised to 230° C. and after 30 minutes the heat was removed. Purification by chromatography on silica gel with heptane/ethyl acetate as eluent gave 0.768 g (yield 38%) of the desired product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:17]([C:32]([NH2:34])=[O:33])=[N:18][CH:19]=[C:20]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=3)[N:21]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]1.[CH3:35][N:36]1[CH2:40][CH2:39][CH2:38][C:37]1=O.N1C=CC(B(O)O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:14][N:11]1[CH2:12][CH2:13][N:8]([C:7]2[CH:6]=[CH:5][C:4]([NH:15][C:16]3[C:17]([C:32]([NH2:34])=[O:33])=[N:18][CH:19]=[C:20]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=4)[N:21]=3)=[CH:3][C:2]=2[C:39]2[CH:40]=[CH:35][N:36]=[CH:37][CH:38]=2)[CH2:9][CH2:10]1
Reactant: CN1CCCC1=O
Reactant: CN1CCN(c2ccc(Nc3nc(Oc4cccc([N+](=O)[O-])c4)cnc3C(N)=O)cc2Br)CC1
Agent: O=C([O-])[O-]
Agent: OB(O)c1ccncc1
Agent: [Na+]
Solvent: O
Product: CN1CCN(c2ccc(Nc3nc(Oc4cccc([N+](=O)[O-])c4)cnc3C(N)=O)cc2-c2ccncc2)CC1
Temperature: 140 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-{[3-bromo-4-(4-methylpiperazin-1-yl)phenyl]amino}-5-(3-nitrophenoxy)pyrazine-2-carboxamide (500 mg), and N-methylpyrrolidone (5 mL) were added pyridin-4-ylboronic acid (407 mg), tetrakistriphenylphosphine palladium (0) (164 mg), and a 2 M aqueous sodium carbonate solution (2.84 mL), followed by stirring in a microwave reaction device at 140° C. for 1 hour. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform:methanol:28% aqueous ammonia=1:0:0-15:1:0.1) to obtain 3-{[4-(4-methylpiperazin-1-yl)-3-(pyridin-4-yl)phenyl]amino}-5-(3-nitrophenoxy)pyrazine-2-carboxamide (64 mg) as a yellow solid.
Reaction SMILES: [C:1]1([C:7]2[O:8][N:9]=[C:10]3[C:15]([CH2:16][C:17]#[N:18])=[CH:14][CH:13]=[CH:12][C:11]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:19].[K+].O>C(O)(C)(C)C>[C:1]1([C:7]2[O:8][N:9]=[C:10]3[C:15]([CH2:16][C:17]([NH2:18])=[O:19])=[CH:14][CH:13]=[CH:12][C:11]=23)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [OH-]
Reactant: N#CCc1cccc2c(-c3ccccc3)onc12
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: NC(=O)Cc1cccc2c(-c3ccccc3)onc12
Yield: 11.7 %

Procedure:
A slurry of 4.0 g (0.017 mole) of 3-phenyl-2,1-benzisoxazol-7-acetonitrile in 175 ml of t-butanol was heated to reflux and treated with 5 g (0.09 mole) of powdered potassium hydroxide. The deep blue colored reaction mixture was heated at reflux for 0.5 hr, cooled and poured into 800 ml of water. The mixture was extracted with three 100 ml portions of methylene chloride. The combined extracts were washed with water, dried over sodium sulfate, and concentrated to give a brown solid as residue. The solid was recrystallized from 2-propanol (charcoal) and then subjected to vacuum sublimation at 160°-170° C. to yield 0.5 g (12%) of an off-white powder, m.p. 191°-192° C. after recrystallization from absolute ethyl alcohol.
Reaction SMILES: C(OC([N:11]1[CH2:19][C:18]2([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:13]([CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>[C].[Pd].CO>[C:24]([O:23][C:21]([NH:20][C:18]12[CH2:19][NH:11][CH2:12][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17]2)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)NC12CCCCC1CN(C(=O)OCc1ccccc1)C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC12CCCCC1CNC2

Procedure:
A 10% palladium-carbon catalyst (80.0 mg, 20 wt %) was added to a solution of 8-benzyloxycarbonyl-1-tert-butoxycarbonylamino-8-azabicyclo[4.3.0]nonane (optical isomer A) (400 mg, 1.07 mmol) in methanol (10.7 mL) in a nitrogen atmosphere. After the atmosphere was replaced with hydrogen, the mixture was stirred in a hydrogen atmosphere at room temperature for one hour. After the atmosphere was replaced with nitrogen, the reaction solution was filtered through Celite and concentrated under reduced pressure to give the title compound quantitatively.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]([B:22]2[O:26][C:25]([CH3:28])(C)C(C)(C)[O:23]2)=[C:15]([CH:18]=[CH:19][C:20]=1[F:21])C=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:31](C)([O-:33])=[O:32].[OH-].[Na+].C1COCC1>O>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]2[B:22]([OH:23])[O:26][CH:25]([CH2:28][N+:31]([O-:33])=[O:32])[C:15]=2[CH:18]=[CH:19][C:20]=1[F:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[N+](=O)[O-]
Reactant: CC1(C)OB(c2c(C=O)ccc(F)c2OCCCOCc2ccccc2)OC1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])CC1OB(O)c2c1ccc(F)c2OCCCOCc1ccccc1
Yield: 93.8 %

Procedure:
Synthesized according to the methods of general procedure 8 in U.S. Pat. Pub. No. 20090227541 (U.S. patent application Ser. No. 12/142,692) using the following reactants and amounts: 3-(3-benzyloxy-propoxy)-4-fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (0.40 g, 0.966 mmol), nitromethane (0.15 mL, 2.89 mmol), NaOH (0.038 g, 0.96 mmol), THF (10 mL), water (10 mL). This generated 0.34 g (94% yield) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.83 (s, 1H), 7.32-7.02 (m, 7H), 5.78-5.75 (m, 1H), 5.28-5.23 (m, 1H), 4.60-4.56 (m, 1H), 4.42 (s, 2H), 4.37 (brs, 2H), 3.57 (brs, 2H), 1.92 (brs, 2H). 19F NMR (376 MHz, DMSO-d6 with D2O) δ (ppm): −132.3 (1F).
Reaction SMILES: [CH3:1][C:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH2:3].CC(=CCCCC)C.S(=O)(=O)(O)O.[NH2:22][CH2:23][C:24]#[N:25].S(=O)(=O)(O)[OH:27]>C(O)(=O)C>[NH2:25][CH2:24][C:23]([NH:22][C:2]([CH3:1])([CH3:3])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[O:27]
Reactant: N#CCN
Reactant: C=C(C)CCCCC
Reactant: O=S(=O)(O)O
Agent: CCCCC=C(C)C
Solvent: CC(=O)O
Product: CCCCCC(C)(C)NC(=O)CN
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture (1:1.1) of 2-methylhept-1-ene and 2-methylhept-2-ene (4.0 g) was added to a suspension of aminoacetonitrile bisulphate (5.5 g; 1 mol equiv.) in acetic acid (22 ml). The resultant mixture was warmed to 40°. Conc. sulphuric acid (4.5 ml) was then added over 10 minutes with stirring, so that the temperature did not rise above 70°. The mixture was left for 1 hour and then poured into ice-water (200 g). The aqueous phase was washed with ether (2×100 ml), basified with 10 N sodium hydroxide solution (100 ml) (pH 14), and extracted with ether (3×100 ml). The combined ether extracts were washed with water (50 ml), dried, and evaporated in vacuo (Buchi; 20°) to give the product as a yellow oil, which was dried at 0.2 mm/0.5 h/r.t. By t.l.c., i.r. and n.m.r. this product was identical with 2-amino-N-(1,1-dimethylhexyl)acetamide prepared from 2-methylheptan-2-ol.
Reaction SMILES: [PH2:1]([OH:3])=[O:2].[C:4]1([CH2:10][CH2:11][CH:12]=[CH2:13])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S(OOS([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].C(N(CC)CC)C>C(#N)C>[C:4]1([CH2:10][CH2:11][CH2:12][CH2:13][P:1]([OH:3])[OH:2])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=[PH2]O
Reactant: C=CCCc1ccccc1
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: OP(O)CCCCc1ccccc1
Temperature: 77 °C
Yield: 87.6 %

Procedure:
To a 30 wt % aqueous solution of hypophosphorous acid (41.8 ml, 0.19 moles) in acetonitrile (100 ml) was added 4-phenyl-1-butene (5 gm, 0.038 moles) and sodium persulfate (1.8 gm, 0.00756 moles). To the stirred mixture triethylamine was added and the pH of the reaction mixture was adjusted to 6.5±0.5. The reaction mixture was heated at 77° C. for 15 minutes for the reaction to be complete. Acetonitrile was distilled off at 40° C. under vacuum and the reaction mixture was diluted with water (20 ml). The pH of the mixture was adjusted to 8.5 with 50% aqueous sodium hydroxide followed by acidification to a pH of 5.0±0.2. The aqueous medium was extracted with dichloromethane (20 ml) and kept aside. The pH of the aqueous layer was adjusted to 1-1.5 using conc. H2SO4 and reextracted with dichloromethane (2×20 ml). The total organic layers were combined, dried over anhydrous sodium sulfate and the solvent distilled off to yield 6.6 gm (88.0%) of the title compound as an oil, having a purity 97.6%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[C:16]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:15]=2[C:29]#[N:30])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[C:16]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:15]=2[CH2:29][NH2:30])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(F)ccc(NCc3ccccc3)c2C#N)CC1
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2c(F)ccc(NCc3ccccc3)c2CN)CC1

Procedure:
To 288 mg (0.7 mmol) of 4-(3-benzylamino-2-cyano-6-fluoro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester dissolved in 7 mL tetrahydrofuran was added 1.4 mL (2 eq., 1.4 mmol, 1M in tetrahydrofuran) borane. The mixture was refluxed 10 hours and quenched with methanol, partitioned between ethyl acetate and water, dried over magnesium sulfate and concentrated to yield crude 4-(2-aminomethyl-3-benzylamino-6-fluoro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester, which was used directly in the following step.