Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:25].[CH3:26][O:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([CH3:43])[N:29]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C(OCC)(=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>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:32]5[CH:31]=[C:30]([CH3:43])[N:29]=[C:28]([O:27][CH3:26])[CH:33]=5)[C:3]([CH3:25])=[CH:4][CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)n1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
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: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1cc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2C)cc(C)n1
Temperature: 80 °C
Yield: 86.6 %

Procedure:
To N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (200 mg, 0.545 mmol), 2-methoxy-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (408 mg, 1.636 mmol) and tetrakis(triphenylphosphine)palladium (0) (64 mg, 0.055 mmol) in 1,2-dimethoxyethane (3.3 mL), 2 M Na2CO3 (818.0 μL, 1.63 mmol) was added. The reaction mixture was stirred and heated at 80° C. for 68 hours under N2 atmosphere. The reaction mixture was diluted with ethyl acetate (5 mL), dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-15% ethyl acetate in hexane) to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-methoxy-3,6′-dimethyl-2,4′-bipyridin-6-yl)cyclopropanecarboxamide (214 mg, 86.5%). ESI-MS m/z calc. 453.4. found 454.5 (M+1)+, retention time 1.81 minutes.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1.Cl.[NH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(N(CC)CC)C>O1CCOCC1>[N+:8]([C:7]1[C:2]([NH:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[N:3][CH:4]=[C:5]([N+:11]([O-:13])=[O:12])[CH:6]=1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)CCCN
Reactant: O=[N+]([O-])c1cnc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCCNc1ncc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A suspension of 3 g (14.74 mmol) of 2-chloro-3,5-dinitropyridine in dioxane is admixed with 3.46 g (17.69 mmol) of tert-butyl 4-aminobutanoate hydrochloride and then with 4.21 ml (22.11 mmol) of triethylamine. The reaction mixture is stirred at 60° C. for 3 hours.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].[CH2:8]([C:11]1[C:19]2[O:18][N:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[C:15]=2[CH:14]=[CH:13][C:12]=1[O:24][CH2:25][CH2:26][CH2:27]Br)[CH2:9][CH3:10]>>[CH2:8]([C:11]1[C:19]2[O:18][N:17]=[C:16]([C:20]([F:21])([F:23])[F:22])[C:15]=2[CH:14]=[CH:13][C:12]=1[O:24][CH2:25][CH2:26][CH2:27][N:4]1[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]1)[CH2:9][CH3:10]
Reactant: CCCc1c(OCCCBr)ccc2c(C(F)(F)F)noc12
Reactant: O=C1CNCCN1
Product: CCCc1c(OCCCN2CCNC(=O)C2)ccc2c(C(F)(F)F)noc12

Procedure:
4-(3-{[7-Propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)piperazine-2-one was prepared as for Example 10 from piperazine-2-one and the bromide from Example 7. After aqueous work-up and silica gel chromatography, the title compound was obtained.
Reaction SMILES: [CH3:1][CH2:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH3:7].Cl.[NH2:10][OH:11]>CO>[CH3:1][CH2:2][C:3](=[N:10][OH:11])[CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: NO
Reactant: CCCCC(=O)CC
Agent: Cl
Solvent: CO
Product: CCCCC(CC)=NO

Procedure:
A mixture of (R)-1-azabicyclo 2.2.1!heptan-3-one (U.S. Pat. No. 5,306,718) (2.22 g, 20 mmol) and hydroxylamine hydrochloride (1.39 g, 20 mmol) in MeOH (75 mL) is stirred at 25° C. for 18 hours. The solvent is removed under reduced pressure, the residual solid dissolves in saturated Na2CO3, and is extracted with CHCl3. The organic extracts are dried (Na2CO3), and concentrated to give the oxime. The aqueous layer is concentrated, and re-extracted with CHCl3 to yield additional product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2[CH2:7][C:8](=[O:17])[N:9]([CH2:12][CH2:13][CH2:14][NH:15][CH3:16])[CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH2:32]C[Cl:34])[CH:27]=[CH:28][C:29]=1[O:30][CH3:31].[CH2:35](Cl)[Cl:36]>CC(C)=O>[ClH:34].[ClH:36].[CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2[CH2:7][C:8](=[O:17])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:35])[CH2:16][CH2:32][C:26]3[CH:27]=[CH:28][C:29]([O:30][CH3:31])=[C:24]([O:23][CH3:22])[CH:25]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1ccc(CCCl)cc1OC
Reactant: ClCCl
Reactant: CNCCCN1CCc2cc(OC)c(OC)cc2CC1=O
Solvent: CC(C)=O
Product: COc1ccc(CCN(C)CCCN2CCc3cc(OC)c(OC)cc3CC2=O)cc1OC
Product: Cl

Procedure:
22 gm (0.075 mol) of N-[3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-propyl]-methylamine were heated with 7.2 gm (0.036 mol) of 2-(3,4-dimethoxyphenyl)-ethyl-chloride for 20 hours at 140° C. After dissolving the reaction product in methylene chloride, the solution was washed twice with 2N sodium hydroxide and twice with water, dried over sodium sulfate and evaporated. The residue was purified by chromatography on silica gel (particle size: 0.063-0.2 mm; eluant; methylene chloride/methanol=10:1). The product thus obtained was dissolved in acetone, and the dihydrocyloride was precipitated with ethereal hydrochloric acid.
Reaction SMILES: C1(S([N:10]2[CH:14]=[C:13]([C:15]([C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=3)=[O:16])[N:12]=[C:11]2[C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31](S(C3C=CC=CC=3)(=O)=O)[CH:30]=2)(=O)=O)C=CC=CC=1.[OH-].[Na+]>C(O)C.O>[NH:31]1[C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:29]([C:11]2[NH:10][CH:14]=[C:13]([C:15]([C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=3)=[O:16])[N:12]=2)=[CH:30]1
Reactant: COc1cc(C(=O)c2cn(S(=O)(=O)c3ccccc3)c(-c3cn(S(=O)(=O)c4ccccc4)c4ccccc34)n2)cc(OC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(C(=O)c2c[nH]c(-c3c[nH]c4ccccc34)n2)cc(OC)c1OC
Reaction time: 8 h
Yield: 60 %

Procedure:
To a solution of (1-(phenylsulfonyl)-2-(1-(phenylsulfonyl)-1H-indol-3-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (17yaa) (1 mmol) in ethanol (40 mL) and water (4 mL) was added sodium hydroxide (10 equiv, 10 mmol) and stirred overnight under refluxing condition in darkness. The reaction mixture was diluted by 50 mL of water and extracted by ethyl acetate (200 mL). The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by flash column chromatography (hexane:ethyl acetate 1:1) to give a yellow solid. Yield: 60%. 1H NMR (500 MHz, CD3OD) δ 8.31 (d, J=6.5 Hz, 1H), 7.99 (s, 1H), 7.90 (s, 1H), 7.48-7.52 (m, 3H), 7.24-7.28 (m, 2H), 4.00 (s, 6H), 3.93 (s, 3H). MS (ESI) calcd for C21H19N3O4 377.1. Found 400.1 [M+Na]+. Mp 208-210° C.
Reaction SMILES: [C:1]12([C:11]3[CH:31]=[CH:30][C:14]([C:15]([O:17][NH:18][C:19]([C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[NH:26][CH:25]=[CH:24]5)=[NH:20])=O)=[CH:13][C:12]=3[O:32][CH3:33])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>C1(C)C=CC=CC=1>[NH:26]1[C:27]2[C:23](=[CH:22][C:21]([C:19]3[N:20]=[C:15]([C:14]4[CH:30]=[CH:31][C:11]([C:1]56[CH2:2][CH:3]7[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]7)[CH2:8]5)[CH2:10]6)=[C:12]([O:32][CH3:33])[CH:13]=4)[O:17][N:18]=3)=[CH:29][CH:28]=2)[CH:24]=[CH:25]1
Reactant: COc1cc(C(=O)ONC(=N)c2ccc3[nH]ccc3c2)ccc1C12CC3CC(CC(C3)C1)C2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1cc(-c2nc(-c3ccc4[nH]ccc4c3)no2)ccc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Yield: 96.2 %

Procedure:
The suspension of the product of Step C (0.13 g; 0.293 mmol) and 1 M TBAF in THF (0.3 ml; 0.3 mmol) in anhydrous toluene (5 ml) was refluxed for 1 h under N2, cooled to room temperature and evaporated to dryness under reduced pressure. The residue was purified by FCC (SiO2; CH2Cl2) to give the title compound (0.12 g; 99%) as a colourless solid. 1H-NMR (CDCl3) 1.78 (s, 6H); 2.01-2.16 (m, 9H); 3.96 (s, 3H); 6.66 (m, 1H); 6.98 (d, 1H, J=8.6 Hz); 7.26 (m, 1H); 7.36 (d, 1H, J=8.14 Hz); 7.48 (d, 1H, J=8.14 Hz); 7.68 (d, 1H, J=1.6 Hz; 7.77 (dd, 1H, J=1.6, 8.1 Hz); 8.01 (dd, 1H, J=1.6, 8.1 Hz); 8.32 (broad s, 1H); 8.51 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])=[CH:22][CH:21]=1>C(COC)OC>[Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:15])[CH:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([F:32])([F:33])[C:28]([F:29])([F:30])[F:31])=[CH:22][CH:21]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)C(F)(F)Cc1ccc(CBr)cc1
Reactant: CCOC(=O)CC(=O)c1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C(Cc1ccc(CC(F)(F)C(F)(F)F)cc1)C(=O)c1cccc(Cl)c1
Yield: 85.6 %

Procedure:
A solution of ethyl 3-(3-chlorophenyl)-3-oxopropionate (2.74 g, 12.08 mmol) in dimethoxyethane (30 ml) was ice-cooled, and sodium hydride (60%, 0.49 g, 12.08 mmol) was added, and the mixture was stirred under ice-cooling for 30 min. A solution of 1-(bromomethyl)-4-(2,2,3,3,3-pentafluoropropyl)benzene (3.66 g, 12.08 mmol) in dimethoxyethane (15 ml) was added, and the mixture was stirred overnight at room temperature. After completion of the reaction, the reaction was quenched with 0.5N hydrochloric acid. The mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=15:1, 10:1) to give ethyl 3-(3-chlorophenyl)-3-oxo-2-[4-(2,2,3,3,3-pentafluoropropyl)benzyl]propionate (4.64 g, 86%) as colorless crystals.
Reaction SMILES: [C:1](=[O:34])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][C@H:3]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([F:23])([F:22])[F:21])[CH2:15][C:6]2[C:7]3[CH:8]=[N:9][NH:10][C:11]=3[C:12]([Cl:14])=[CH:13][C:5]=2[CH2:4]1.CN(C=O)C.C(N(CC)CC)C.[NH:47]1[CH2:52][CH2:51][CH:50]([N:53]2[C:61]3[C:56](=[N:57][CH:58]=[CH:59][CH:60]=3)[NH:55][C:54]2=[O:62])[CH2:49][CH2:48]1>>[O:62]=[C:54]1[NH:55][C:56]2=[N:57][CH:58]=[CH:59][CH:60]=[C:61]2[N:53]1[CH:50]1[CH2:51][CH2:52][N:47]([C:1]([O:2][C@H:3]2[C:17](=[O:18])[N:16]([CH2:19][C:20]([F:23])([F:21])[F:22])[CH2:15][C:6]3[C:7]4[CH:8]=[N:9][NH:10][C:11]=4[C:12]([Cl:14])=[CH:13][C:5]=3[CH2:4]2)=[O:34])[CH2:48][CH2:49]1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)O[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(CC(F)(F)F)C1=O
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(O[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(CC(F)(F)F)C1=O)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Reaction time: 12 h
Yield: 80 %

Procedure:
(R)-4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl 4-nitrophenyl carbonate (115 mg, 0.23 mmol) in DMF (10.00 mL, 129 mmol) was added triethylamine (0.128 mL, 0.920 mmol) followed by 1-(piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one, 1.00HCl (70.3 mg, 0.276 mmol). After 12 h, the solvent was removed and the product was purified by flash chromatography using 5% methanol in dichloromethane to give (R)-4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (106 mg, 0.183 mmol, 80% yield). 1H NMR (500 MHz, CD3OD): in δ 8.29 (s, 1H), 8.03 (br, 1H), 7.96 (d, J=5.5 Hz, 1H), 7.71 (m, 1H), 7.27 (s, 1H), 7.13-7.12 (m, 1H), 6.10 (m, 1H), 5.44 (d, J=17 Hz, 1H), 4.88 (d, J=17 Hz, 1H), 4.72-4.60 (m, 2H), 4.50-4.39 (m, 1H), 4.38-4.22 (m, 1H), 4.21-4.02 (m, 1H), 3.40-3.40 (m, 1H), 3.39-3.27 (m, 2H), 3.23-2.97 (m, 2H), 2.71-2.23 (m, 2H), 1.95-1.74 (m, 2H); MS (ESI) 578 (M+H); Rf=2.15.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[NH:9]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2[C:20]([OH:22])=[O:21])[C:12](=O)[C:10]1=O.O.[C:24](O)(=O)C>>[CH:3]1[CH:4]=[CH:5][CH:6]=[C:1]2[C:2]=1[N:7]=[C:12]1[C:14]3[C:19](=[C:18]([C:20]([O:22][CH3:24])=[O:21])[CH:17]=[CH:16][CH:15]=3)[N:9]=[C:10]1[NH:8]2
Reactant: Nc1ccccc1N
Reactant: CC(=O)O
Reactant: O=C1Nc2c(C(=O)O)cccc2C1=O
Solvent: O
Product: COC(=O)c1cccc2c3nc4ccccc4[nH]c-3nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 3.96 g of 1,2-phenylenediamine and 7.00 g of 7-isatincarboxylic acid in 70 ml of acetic acid was heated under reflux for an hour. After completion of the reaction, the reaction solution was allowed to cool to room temperature, followed by addition of water, and resulting precipitate was collected by filtration. The thus obtained 7-indolo[2,3-b]quinolinecarboxylic acid and 170 ml of thionyl chloride were refluxed for 2 hours, and the excess thionyl chloride was evaporated. The residue, after addition of 250 ml of methanol, was stirred overnight. After addition of water, the resulting precipitate was collected by filtration, and purified by silica gel column chromatography to give methyl 7-indolo[2,3-b]quinoxalinecarboxylate.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[Cl:7][C:8]1[C:13]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)(=[O:17])=[O:16])=[CH:12][C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][N:9]=1.Br[C:36]1[CH:37]=[C:38]2[C:43](=[CH:44][CH:45]=1)[N:42]=[C:41]([NH2:46])[CH:40]=[CH:39]2.CCO>C(Cl)Cl.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>[NH2:46][C:41]1[CH:40]=[CH:39][C:38]2[C:43](=[CH:44][CH:45]=[C:36]([C:11]3[CH:12]=[C:13]([NH:14][S:15]([C:18]4[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=4)(=[O:16])=[O:17])[C:8]([Cl:7])=[N:9][CH:10]=3)[CH:37]=2)[N:42]=1
Reactant: COc1ccc(S(=O)(=O)Nc2cc(B3OC(C)(C)C(C)(C)O3)cnc2Cl)cc1
Reactant: Nc1ccc2cc(Br)ccc2n1
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: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)Nc2cc(-c3ccc4nc(N)ccc4c3)cnc2Cl)cc1
Temperature: 90 °C
Yield: 11.6 %

Procedure:
A reaction tube was charged with sodium carbonate (353 μl, 706 μmol), Pd(Ph3P)4 (16 mg, 14 μmol), N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-4-methoxybenzenesulfonamide (100 mg, 235 μmol), 6-bromoquinolin-2-amine (53 mg, 235 μmol) and 1.2 mL EtOH. The tube was sealed and the mixture was heated at 90° C. for 2 h. The mixture was diluted with CH2Cl2 and washed with water. The organic portion was dried with MgSO4, filtered and concentrated. The crude material was dissolved in MeOH/DMSO and purified by reverse phase chromatography, 10-90% ACN/0.1% TFA in water over 15 min. The aqueous portion was brought to ˜pH 7 and extracted. The organic portion was dried, filtered and concentrated to provide N-(5-(2-aminoquinolin-6-yl)-2-chloropyridin-3-yl)-4-methoxybenzenesulfonamide (12 mg, 12% yield) as a light yellow solid. MS (ESI pos. ion) m/z calc'd for C21H17ClN4O3S: 440.9/442.9; found 441.0/443.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.88 (s, 3 H), 6.88 (br s, 2 H), 6.89 (d, 1 H, J=8), 7.15-7.18 (m, 2 H), 7.61 (d, 1 H, J=8), 7.75-7.80 (m, 3 H), 7.97-8.00 (m, 2 H), 8.03-8.06 (m, 1 H), 8.62-8.63 (m, 1 H), 10.46 (br, s, 1 H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[S:8][CH:9]=[CH:10][C:11]=1[NH2:12].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22](O)=[O:23])=[CH:17][CH:16]=1>>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([NH:12][C:11]2[CH:10]=[CH:9][S:8][C:7]=2[C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)=[O:23])=[CH:17][CH:16]=1
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: Nc1ccsc1-c1cnccn1
Product: COc1ccc(CC(=O)Nc2ccsc2-c2cnccn2)cc1

Procedure:
The title compound was prepared from 2-(pyrazin-2-yl)thiophen-3-amine and 2-(4-methoxyphenyl)acetic acid according to protocol B and was purified by HPLC. Method [7] Retention time 5.91 min by HPLC (MH+ 326). 1H NMR (300 MHz, DMSO) δ s (11.02, 1H), 8.81 (d, J=0.9 Hz, 1H), 8.45 (d, J=2.7 Hz, 1H), 8.26 (m, 1H), 7.92 (d, J=5.4 Hz, 1H), 7.74 (d, J=5.4 Hz, 1H), 7.33 (d, 8.7 Hz, 2H), 6.99 (d, J=8.7 Hz, 2H), 3.78 (s, 3H), 3.72 (s, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][C:18]=1[O:19][CH2:20][CH3:21])[C:7]([NH:9][C:10]([CH3:15])([CH3:14])[C:11]([OH:13])=O)=[O:8])[CH3:2].[CH2:22]([C:29]1[S:33][C:32]([NH2:34])=[N:31][C:30]=1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>C(#N)C.O>[CH2:22]([C:29]1[S:33][C:32]([NH:34][C:11]([C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:16]=[CH:17][C:18]([O:19][CH2:20][CH3:21])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=2)([CH3:15])[CH3:14])=[O:13])=[N:31][C:30]=1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Nc1nc(-c2ccccc2)c(Cc2ccccc2)s1
Reactant: CCOc1ccc(C(=O)NC(C)(C)C(=O)O)cc1OCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: CCOc1ccc(C(=O)NC(C)(C)C(=O)Nc2nc(-c3ccccc3)c(Cc3ccccc3)s2)cc1OCC
Temperature: 50 °C
Reaction time: 48 h

Procedure:
150 mg of 2-(3,4-Diethoxy-benzoylamino)-2-methyl-propionic acid and 130 mg of 5-Benzyl-4-phenyl-thiazol-2-ylamine (WO2006082952) were stirred in 2 ml of acetonitrile at room temperature. 120 mg of EDCl and 100 mg of HOBT were added and the reaction mixture was stirred at 50° C. for 2 days and cooled to room temperature. It was diluted with water and the resulting precipitates were collected by filtration followed by washing with water. The filter cake was then purified by column chromatography (heptane/ethyl acetate=3/1) to provide the title compound. 1H NMR (400 MHz. CD3OD) δ 1.34-1.54 (m, 3H) 1.44 (d, J=5.31 Hz, 3H) 1.65 (s, 7H) 4.14 (qd, J=6.95, 2.53 Hz, 4H) 4.23 (s, 2H) 7.01 (d, J=8.46 Hz, 1H) 7.16-7.26 (m, 3H) 7.26-7.45 (m, 6H) 7.47-7.67 (m, 4H). m/z 545.1 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:53][C:54]1[CH:59]=[CH:58][C:57]([CH:60]([C:67]2[CH:72]=[CH:71][C:70]([F:73])=[CH:69][CH:68]=2)[N:61]2[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]2)=[CH:56][CH:55]=1>CN(C=O)C.C(OCC)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:17]([N:64]1[CH2:63][CH2:62][N:61]([CH:60]([C:67]2[CH:72]=[CH:71][C:70]([F:73])=[CH:69][CH:68]=2)[C:57]2[CH:56]=[CH:55][C:54]([F:53])=[CH:59][CH:58]=2)[CH2:66][CH2:65]1)=[O:19])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 0.58 h
Yield: 95.8 %

Procedure:
N-tert-Butoxycarbonyl-L-phenylalanine (4.60 g, 17.3 mmol, Bachem Inc., Torrance, Calif.) was dissolved in dry DMF (33 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (6.04 mL, 34.7 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (6.58 g, 17.4 mmol). The resulting reaction mixture was stirred at that temperature for 35 minutes; solid 1-bis(4-fluorophenyl)methyl piperazine (5.00 g, 17.3 mmol) was then added. After stirring for, sequentially, 15 minutes at 0° C. and 30 minutes at ambient temperature, reaction mixture was mixed with 120 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×120 mL), brine (2×120 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was further purified by flash chromatography (30% EtOAc in hexanes) to provide 8.88 g (95%) of the pure titled compound as a off-white foam: mp 54-74° C. APCI-MS m/z 536.4 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:7][C@H:6]1[C:8]([OH:10])=O)=[O:4].[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.CN1CCOCC1.[CH3:40][C@H:41]1[CH2:46][CH2:45][C@H:44]([NH2:47])[CH2:43][CH2:42]1>CN(C=O)C>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:7][C@H:6]1[C:8](=[O:10])[NH:47][CH:44]1[CH2:45][CH2:46][CH:41]([CH3:40])[CH2:42][CH2:43]1)=[O:4]
Reactant: C[C@H]1CC[C@H](N)CC1
Reactant: COC(=O)[C@@H]1C[C@H]1C(=O)O
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)[C@@H]1C[C@H]1C(=O)NC1CCC(C)CC1
Reaction time: 3 h
Yield: 95.6 %

Procedure:
Stir a solution of trans-cyclopropane-1,2-dicarboxylic acid monomethyl ester (Example 3a) (3.0 g, 20.8 mmol) and TOTU (8.5 g, 26 mmol) in DMF (300 mL) at ambient temperature for 20 min at which time add N-methylmorpholine (2.4 mL 22.9 mmol) and trans 4-methylcyclohexylamine 3.06 g, 27.0 mmol). After 3 h, remove the solvent and dissolve the residue in H2O/EtOAc. Extract the aqueous layer 3 more times with EtOAc and combine the extracts. Wash the extract with saturated NaHCO3 solution, brine and dry over MgSO4. Concentrate the solvent to afford the crude product, and purify by column chromatography over silica gel to give 4.76 g (95%) of colorless crystals, m/z=240 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([N:12]2[CH2:17][CH2:16][C@:15]([CH2:24][CH2:25][CH2:26][OH:27])([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:14][C:13]2=[O:28])[CH3:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:29][Mg]Br>C1COCC1>[OH:3][C:1]([C:4]1[CH:5]=[CH:6][C:7]([C@@H:10]([N:12]2[CH2:17][CH2:16][C@:15]([CH2:24][CH2:25][CH2:26][OH:27])([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:14][C:13]2=[O:28])[CH3:11])=[CH:8][CH:9]=1)([CH3:29])[CH3:2]
Reactant: C[Mg]Br
Reactant: CC(=O)c1ccc([C@H](C)N2CC[C@](CCCO)(c3ccccc3)OC2=O)cc1
Solvent: C1CCOC1
Product: C[C@@H](c1ccc(C(C)(C)O)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 12.6 %

Procedure:
To a solution of (R)-3-((S)-1-(4-acetylphenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one (40 mg, 0.1 mmol) in THF (10 mL) was added dropwise methylmagnesium bromide (3 M, 1 mL, 1 mmol) at −78° C. under N2. The mixture was stirred at rt for 2 days. The reaction was quenched with water, and the layers were separated. The aqueous layer was extracted with EtOAc (3×). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated to give the crude product, which was purified by preparative HPLC to give (R)-3-((S)-1-(4-(2-hydroxypropan-2-yl)phenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one (5 mg, 13%). 1H NMR (CDCl3): 1.31 (m, 1H), 1.44 (m, 3H), 1.64 (m, 1H), 1.93 (m, 2H), 2.11-2.25 (m, 3H), 2.82 (m, 1H), 3.51 (m, 2H), 5.58 (m, 1H), 6.81 (m, 2H), 7.14 (m, 2H), 7.27 (m, 5H). LC-MS Method 2 tR=1.141, min, m/z=420.