Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[N:8][NH:9]2)=[CH:5][CH:4]=1.Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].CCOC(C)=O>CN(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+]>[C:12]([C:7]1[C:6]2[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:9]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:8]=1)(=[O:16])[CH:13]([CH3:14])[CH3:15]
Reactant: CCOC(=O)CBr
Reactant: COc1ccc2c(C(=O)C(C)C)n[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1nc(C(=O)C(C)C)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolve 5.456 g of 1-(6-methoxy-1H-indazol-3-yl)-2-methylpropan-1-one in 100 mL anhydrous DMF. Weigh in 8.96 g cesium carbonate followed by 4.593 g ethyl bromoacetate. The resulting mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure. Partition the residue between EtOAc and water. Extract the aqueous layer with EtOAc several times. The combined organic extract was washed with water (3×) and saturated brine, dried over anhydrous Na2SO4, and evaporated to give the crude product. The title compound was obtained by recrystallization from 40 mL 4:1 hexanes and EtOAc. 1H NMR (CDCl3, 500 MHz) δ 8.26 (d, 8.9 Hz, 1H), 7.00 (dd, 2.1 & 9.0 Hz, 1H), 6.685 (d, 2.1 Hz, 1H), 5.17 (s, 2H), 4.28 (q, 7.1 Hz, 2H), 3.90 (s, 3H), 3.87 (heptet, 6.9 Hz, 1H), 1.29 (t, 7.1 Hz, 3H), 1.28 (d, 6.8 Hz, 6H). LC-MS: 3.51 min. (m/Z=305.1, 327.0).
Reaction SMILES: Br[C:2]1[C:3]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:4][C:5]2[N:10]([CH2:11][CH3:12])[C:9](=[O:13])[CH2:8][O:7][C:6]=2[N:14]=1.CC1(C)C(C)(C)OB([C:29]2[CH:43]=[CH:42][C:32]([CH2:33][NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:31][CH:30]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[CH2:11]([N:10]1[C:9](=[O:13])[CH2:8][O:7][C:6]2[N:14]=[C:2]([C:29]3[CH:43]=[CH:42][C:32]([CH2:33][NH:34][C:35](=[O:41])[O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[CH:31][CH:30]=3)[C:3]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:4][C:5]1=2)[CH3:12]
Reactant: CCN1C(=O)COc2nc(Br)c(-c3ccccc3)cc21
Reactant: CC(C)(C)OC(=O)NCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CCN1C(=O)COc2nc(-c3ccc(CNC(=O)OC(C)(C)C)cc3)c(-c3ccccc3)cc21
Temperature: 50 °C
Yield: 65.3 %

Procedure:
In a 15 mL reaction tube was added 6-bromo-1-ethyl-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (50 mg, 0.150 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (60.0 mg, 0.180 mmol), and CESIUM CARBONATE (244 mg, 0.750 mmol) in a mixture of 1,4-Dioxane (2814 μl) and water (938 μl) to give a colourless solution. This was degassed by bubbling nitrogen for 15 minutes, followed by the addition of PdCl2(dppf)-CH2Cl2Adduct (24.51 mg, 0.030 mmol) and degassing for a further 5 minutes. The reaction mixture was heated to 50° C. under a nitrogen atmosphere for one hour. LC-MS analysis showed reaction completion. The reaction mixture was allowed to cool to room temperature, diluted with water (5 mL) and extracted into ethyl acetate (3×5 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated to dryness under reduced pressure to give an off-white solid. The resulting residue was purified via Biotage (15-85% cyclohexane:EtOAc; 10 g column) to give the title compound (45 mg, 65.3%) as off-white solid. 1H NMR (500 MHz, CDCl3): 7.31-7.27 (6H, m), 7.19-7.18 (2H, d), 7.11-7.10 (2H, d), 4.87 (2H, s), 4.84 (1H, br), 4.27 (2H, s), 4.03-3.98 (2H, q), 1.45 (9H, br), 1.32-1.30 (3H, t).
Reaction SMILES: Cl[C:2]1[C:3](=[O:8])[NH:4][CH2:5][CH2:6][CH:7]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.C(N(CC)CC)C>C1COCC1>[N:9]1([C:2]2[C:3](=[O:8])[NH:4][CH2:5][CH2:6][CH:7]=2)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: O=C1NCCC=C1Cl
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1NCCC=C1N1CCOCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 43 %

Procedure:
A solution of 3-chloro-5,6-dihydro-1H-pyridin-2-one (44, 1.0 g, 7.6 mmol) in THF (4 mL) was treated with morpholine (663 mg, 0.67 mL, 7.6 mmol, 1.0 equiv) and triethylamine (TEA, 1.54 g, 2.1 mL, 15.2 mmol, 2.0 equiv) at room temperature, and the resulting reaction mixture was warmed up to reflux for 6 h. When HPLC and TLC showed the reaction was deemed complete, the reaction mixture was quenched with water (10 mL) and EtOAc (20 mL), and the resulting mixture was stirred at room temperature for 10 min. The two layers were separated, and the aqueous layer was extracted with EtOAc (3×20 mL). The combined organic extracts were washed with saturated NaCl aqueous solution (5 mL), dried over MgSO4, and concentrated in vacuo. The residue was then purified by flash column chromatography (SiO2, 15-40% EtOAc/hexane gradient elution) to afford the desired 3-morpholin-4-yl-5,6-dihydro-1H-pyridin-2-one (45, 595 mg, 1.384 g theoretical, 43%) as pale-yellow oil, which solidified upon standing at room temperature in vacuo and was found to be essentially pure to do the following reaction without further purification. For 45, CIMS m/z 181 (M+−H, C9H14N2O2).
Reaction SMILES: OC1C=CC(CNC(=O)C2C=CC(NC3C4[N:18]([CH:27]=[CH:28]N=4)[C:19]([C:22]4[CH:23]=[N:24]N[CH:26]=4)=CN=3)=CC=2)=CC=1.[Br:33][C:34]1[N:39]2[CH:40]=[CH:41][N:42]=[C:38]2[C:37]([NH:43][C:44]2[CH:52]=[CH:51][C:47]([C:48]([OH:50])=O)=[CH:46][CH:45]=2)=[N:36][CH:35]=1.NCC1C=NC=CC=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[Br:33][C:34]1[N:39]2[CH:40]=[CH:41][N:42]=[C:38]2[C:37]([NH:43][C:44]2[CH:45]=[CH:46][C:47]([C:48]([NH:24][CH2:23][C:22]3[CH:19]=[N:18][CH:27]=[CH:28][CH:26]=3)=[O:50])=[CH:51][CH:52]=2)=[N:36][CH:35]=1
Reactant: O=C(NCc1ccc(O)cc1)c1ccc(Nc2ncc(-c3cn[nH]c3)n3ccnc23)cc1
Reactant: O=C(O)c1ccc(Nc2ncc(Br)n3ccnc23)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NCc1cccnc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1cccnc1)c1ccc(Nc2ncc(Br)n3ccnc23)cc1

Procedure:
In the same way as described for Compound 90, step 3, using 4-(5-bromoimidazo[1,2-a]pyrazin-8-ylamino)benzoic acid (365 mg, 1.57 mmol), 3-aminomethylpyridine (0.16 mL, 1.57 mmol), N,N-diisopropylethylamine (0.42 mL, 2.35 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (715 mg, 1.9 mmol) and DMF (6 mL). The crude residue is purified using column chromatography, eluting with EtOAc followed by EtOAc:MeOH (95:5) then EtOAc:NH3 (7M in MeOH). The title amide is isolated as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][C:15]([CH3:24])=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[S:14][C:15]([CH3:24])=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1)=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: Cc1sc(N)nc1-c1ccccc1
Product: Cc1sc(NC(=O)c2cc(Br)ccc2O)nc1-c1ccccc1

Procedure:
Using 5-bromosalicylic acid and 2-amino-5-methyl-4-phenylthiazole as the raw materials, the same operation as the example 16 gave the title compound. (2-Amino-5-methyl-4-phenylthiazole: refer to Yakugaku Zasshi, 1961, 81, 1456.)
Reaction SMILES: [CH2:1]([S:8][CH:9]([CH:38]=O)[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:18][C:17]=2[NH:28][S:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)(=[O:31])=[O:30])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:40]1[CH2:45][CH2:44][S:43](=[O:47])(=[O:46])[CH2:42][CH2:41]1.O1CCCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[CH2:1]([S:8][CH:9]([CH2:38][N:40]1[CH2:45][CH2:44][S:43](=[O:47])(=[O:46])[CH2:42][CH2:41]1)[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:18][C:17]=2[NH:28][S:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)(=[O:30])=[O:31])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCOc1cc(NS(=O)(=O)c2ccccn2)c2[nH]c(C(=O)NCC(C=O)SCc3ccccc3)cc2c1
Reactant: O=S1(=O)CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCCOc1cc(NS(=O)(=O)c2ccccn2)c2[nH]c(C(=O)NCC(CN3CCS(=O)(=O)CC3)SCc3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.7 %

Procedure:
A mixture of N-[2-(benzylthio)-3-oxopropyl]-5-(2-methoxyethoxy)-7-[(pyridin-2-ylsulfonyl)amino]-1H-indole-2-carboxamide (500 mg), thiomorpholine 1,1-dioxide (240 mg) and tetrahydrofuran (10 mL) was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (280 mg) was added at room temperature, and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (3:7-1:9, volume ratio) to give the title compound (210 mg, yield 35%) as a colorless amorphous solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][C@H:8]([C:12](=[O:32])[NH:13][C@H:14]([B:19]1[O:27][C@H:26]2[C@:21]([CH3:31])([C@H:22]3[CH2:28][C@@H:24]([CH2:25]2)[C:23]3([CH3:30])[CH3:29])[O:20]1)[CH2:15][CH:16]([CH3:18])[CH3:17])[CH:9]([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].C(N[C@@H](C(O)=O)C(C)C)(OC(C)(C)C)=O>>[C:1]([O:5][C:6](=[O:33])[NH:7][C@@H:8]([C:12](=[O:32])[NH:13][C@H:14]([B:19]1[O:27][C@H:26]2[C@:21]([CH3:31])([C@H:22]3[CH2:28][C@@H:24]([CH2:25]2)[C:23]3([CH3:29])[CH3:30])[O:20]1)[CH2:15][CH:16]([CH3:18])[CH3:17])[CH:9]([CH3:11])[CH3:10])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)C[C@H](NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Agent: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Product: CC(C)C[C@H](NC(=O)[C@H](NC(=O)OC(C)(C)C)C(C)C)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1

Procedure:
The title compound is prepared as described for {(S)-2-Methyl-1-[(R)-3-methyl-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]-dec-4-yl)-butylcarbamoyl]-propyl}-carbamic acid tert-butyl ester (example 1 (c)) but using Boc-D-valine (Fluka).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17](Cl)[N:16]=2)[C:10]=1[C:11]([F:14])([F:13])[F:12])=[O:5])[CH3:2].[F:22][C:23]1[C:28](B(O)O)=[CH:27][CH:26]=[CH:25][N:24]=1.C([O-])([O-])=O.[Na+].[Na+]>C(#N)C>[F:22][C:23]1[C:28]([C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([N:9]3[C:10]([C:11]([F:14])([F:13])[F:12])=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:7]=[N:8]3)[N:16]=2)=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: OB(O)c1cccnc1F
Reactant: CCOC(=O)c1cnn(-c2cccc(Cl)n2)c1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1cnn(-c2cccc(-c3cccnc3F)n2)c1C(F)(F)F
Temperature: 100 °C
Reaction time: 0.83 h

Procedure:
A mixture of the title compound from Example 1 Step A (100 mg, 0.3 mmol), (2-fluoropyridin-3-yl)boronic acid (66 mg, 0.47 mmol), trans dichlorobis(triphenylphosphine) palladium (II) (31.0 mg, 0.05 mmol), Na2CO3 (0.47 mL, 2.0 M aqueous, 0.94 mmol) and acetonitrile (1 mL) in a nitrogen-filled capped vial was stirred at 100° C. After 50 min, the mixture was allowed to cool to ambient temperature, then was concentrated in vacuo. Purification by flash chromatography on silica gel using hexane:EtOAc (6:1 to 4:1 v/v) as mobile phase provided the title compound: LCMS m/z 381.1 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 8.63 (m, 1H), 8.27 (m, 1H), 8.13 (s, 1H), 8.10 (d, J=7.9 Hz, 1H), 8.03 (t, J=7.9 Hz, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.35 (m, 1H), 4.39 (q, J=7.1 Hz, 2H), 1.39 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Si]([O:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][CH:14]([C:22]([OH:24])=[O:23])[C:15]([CH2:20][CH3:21])(O)[C:16]([OH:18])=O)=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.[C:27](OC(=O)C)(=[O:29])[CH3:28]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:27]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][C:14]2[C:22]([O:23][C:16](=[O:18])[C:15]=2[CH2:20][CH3:21])=[O:24])=[CH:25][CH:26]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: CCC(O)(C(=O)O)C(Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1)C(=O)O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCC1=C(Cc2ccc(OC(C)=O)cc2)C(=O)OC1=O
Temperature: 115 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
To the crude 3-(4-t-butyldimethylsilyloxybenzyl)-2-ethyl-2-hydroxysuccinic acid thus obtained was added acetic anhydride (5 mL), and the mixture was stirred at 115° C. for 3 h. The acetic anhydride was evaporated under reduced pressure, and the residue thus obtained was subjected to silica gel column chromatography (toluene-ethyl acetate 19:1→16:1) to give the title compound as oil in an amount of 210 mg (2 step yield: 79%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7](=[O:33])[N:8]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH2:31][CH3:32])[CH:21]=1)[CH2:16][C:17](O)=[O:18])[C:9]2=[O:14])(=[O:3])[CH3:2].C1N=[CH:37][N:36](C(N2C=NC=C2)=O)[CH:35]=1.CNC>C1COCC1>[C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7](=[O:33])[N:8]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:28])[F:29])=[C:22]([O:30][CH2:31][CH3:32])[CH:21]=1)[CH2:16][C:17]([N:36]([CH3:37])[CH3:35])=[O:18])[C:9]2=[O:14])(=[O:3])[CH3:2]
Reactant: CCOc1cc(C(CC(=O)O)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC(F)F
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)N(C)C)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC(F)F
Yield: 65 %

Procedure:
3-(4-Acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-N,N-dimethyl-propionamide was prepared by the procedure of example 13 from 3-(4-acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid (0.5 g, 1.1 mmol), CDI (0.2 g, 0.1.3 mmol) and dimethylamine (2N in THF, 0.7 ml, 1.4 mmol) in THF (10 ml) to give 3-(4-acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-N,N-dimethyl-propionamide (0.35 g, 67% yield): mp, 163-165° C.; 1HNMR (CDCl3): δ1.44 (t, J=7.0 Hz, 3H, OCH2CH3), 2.25 (s, 3H, CH3CO), 2.90 (s, 3H, NCH3), 2.98 (dd, J=5, 15 Hz, 1H, CH2), 3.05 (s, 4H, NCH3+CH2), 3.91 (dd, J=10, 15 Hz, 1H, CH2), 4.09 (q, J=7.0 Hz, 2H, OCH2CH3), 5.81-5.87 (m, 1H, CHN), 6.53 (t, JH-F=75 Hz, 1H, CF2H), 7.11-7.17 (m, 3H, Ar), 7.45 (d, J=7.0 Hz, 1H, Ar), 7.62 (t, J=8.0 Hz, 1H, Ar), 8.73 (d, J=8.8 Hz, 1H, Ar), 9.53 (s, 1H, NHCO). 13CNMR (DMSO-d6): δ 14.5, 24.8, 34.8, 35.5, 37.1, 51.3, 64.7, 111.9, 113.8, 115.4, 116.1, 117.9, 120.1, 120.2, 122.7, 124.7, 131.3, 135.8, 137.5, 138.1, 150.6, 168.1, 169.2, 169.3, 170.0; Anal Calcd for C24H25F2N3O6: C, 58.89; H. 5.15; N, 8.58. Found: C, 58.53; H, 4.78; N, 8.51.
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])[NH:2][NH2:3].C(O)(=O)C.[CH3:17][C:18]([CH:21]=O)([CH3:20])[CH3:19]>CO>[CH2:6]([O:5][C:1]([NH:2]/[N:3]=[CH:17]/[C:18]([CH3:21])([CH3:20])[CH3:19])=[O:4])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)C=O
Reactant: NNC(=O)OCc1ccccc1
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)/C=N/NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
Benzyl carbazate (300 g, 1.81 moles) was dissolved in 1.2 L of methyl alcohol in a 3 L 4-neck flask equipped with reflux condenser, thermometer, magnetic stirring, and a 500 mL addition funnel. Glacial acetic acid (5 mL) was added to the mixture that was then brought to 45° C. Pivaldehyde (248.8 g of solution, 2.17 moles, ca. 75% in t-butanol) was added portionwise over 30 minutes. The reaction was heated at reflux for 30 minutes, while monitoring by TLC. The mixture was allowed to cool to nearly room temperature and was concentrated on a rotary evaporator to a total volume of ca. 700 mL. Ca. 7 g activated charcoal was added at ca. 30° C. The mixture was stirred overnight and filtered through a pad of Celite in a pore size “C” glass fritted Büchner funnel. The solvent was removed in vacuo to leave a light yellow oil that was poured into a crystallizing dish and induced to crystallize by manipulation with a spatula. The material was granulated and residual solvent was allowed to evaporate in air at room temperature for several days, leaving 420.4 g crude product. Recrystallization at room temperature from an initially boiling mixture of 300 mL ethyl acetate and 1 L hexanes produced 363.2 g of (E)-N′-(2,2-dimethyl-propylidene)-hydrazinecarboxylic acid benzyl ester as an off-white solid. A second crop of 43.1 g and identical melting point was obtained from a mixture of ca. 150 mL hexanes and 45 mL ethyl acetate. Total yield: 96.1%. Rf=0.32 (2:1 hexanes:ethyl acetate); mp=74-74.5° C.; 1H NMR (400 MHz, CDCl3) δ 8.0 (1H, br s), 7.4-7.3 (5H, m), 7.1 (1H, s), 5.20 (2H, s), 1.1 (9H, s).
Reaction SMILES: [C:1](=[C:4]([OH:10])[C@H:5]([OH:9])[CH2:6][CH2:7]O)([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:30]N1C(=O)CCC1=O.CCCCCC>C(Cl)Cl>[Br:30][CH2:7][CH2:6][C@@H:5]([OH:9])[C:4](=[C:1]([CH3:3])[CH3:2])[OH:10]
Reactant: CC(C)=C(O)[C@H](O)CCO
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(C)=C(O)[C@H](O)CCBr
Temperature: 0 °C
Yield: 46.8 %

Procedure:
(R)-Isopropylidenebutane-1,2,4-triol (0.3 g, 2.05 mmol) and triphenylphosphine (0.63 g, 2.4 mmol) were dissolved in methylene chloride (5 ml) and cooled to 0° C. and N-bromosuccinimide (0.38 g, 2.16 mmol) was added in small portions with stirring. After additional 1 h of stirring at 0° C. hexane (15 ml) was added and the resulting precipitate was removed by filtration and washed twice with hexane (2×5 ml). The combined hexane solution was passed through a short column of silica gel (5 g). Elution with hexane (15 ml) gave after evaporation and distillation the title compound as a colourless oil (0.2 g, 0.96 mmol, 47%): b.p. 74°-76° C. at 2.7 kPa (20 mm Hg), nD20 =1.4630. {α}D20 =+27.7° (c=20, CHCl3).
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][C:8]2[NH:7][C:6]3[N:11]=[CH:12][C:13]([C:15]4[CH:20]=[CH:19][C:18]([CH2:21][N:22]5[C@H:27]([CH3:28])[CH2:26][CH2:25][CH2:24][C@@H:23]5[CH3:29])=[CH:17][CH:16]=4)=[CH:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1>C(=O)([O-])[O-].[Na+].[Na+].C(#N)C.C(OCC)(=O)C>[CH3:29][C@H:23]1[CH2:24][CH2:25][CH2:26][C@@H:27]([CH3:28])[N:22]1[CH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]2[CH:12]=[N:11][C:6]3[NH:7][C:8]4[CH:9]=[N:10][C:2]([C:34]5[CH:33]=[N:32][N:31]([CH3:30])[CH:35]=5)=[CH:3][C:4]=4[C:5]=3[CH:14]=2)=[CH:16][CH:17]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: C[C@@H]1CCC[C@H](C)N1Cc1ccc(-c2cnc3[nH]c4cnc(Br)cc4c3c2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C[C@@H]1CCC[C@H](C)N1Cc1ccc(-c2cnc3[nH]c4cnc(-c5cnn(C)c5)cc4c3c2)cc1
Temperature: 130 °C
Yield: 31.1 %

Procedure:
A degassed mixture of 6-bromo-3-[4-((2S,6R)-2,6-dimethyl-piperidin-1-ylmethyl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (223 mg, 0.50 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (208 mg, 1.0 mmol), 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (41 mg, 0.05 mmol) in 2N aqueous sodium carbonate solution (6 mL) and acetonitrile (6 mL) was heated under microwave irradiation at 130° C. for 20 minutes. The cooled reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (75 mL). The organic phase was separated, dried over sodium sulfate, filtered and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 25 g column, Biotage, 0-15% methanol in DCM) to afford the title compound as a white solid (70 mg, 31%). 1H NMR (CDCl3 plus CD3OD, 300 MHz): 8.85 (d, J=1.1 Hz, 1H), 8.82-8.77 (m, 2H), 8.33 (d, J=1.1 Hz, 1H), 8.08 (s, 1H), 8.06 (d, J=0.8 Hz, 1H), 7.71-7.65 (m, 2H), 7.56-7.51 (m, 2H), 4.00 (d, J=1.9 Hz, 5H), 2.65-2.52 (m, 2H), 1.72-1.60 (m, 3H), 1.47-1.30 (m, 3H), 1.25 (d, J=6.2 Hz, 6H).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]12[CH2:15][CH:11]3[CH2:12][CH:13]([CH2:14]1)[C:9](C(O)=O)([CH2:10]3)[CH2:8]2.OS(O)(=O)=O.[N-:24]=[N+]=[N-].[Na+]>C(Cl)(Cl)Cl.O>[NH2:24][C:9]12[CH2:10][CH:11]3[CH2:15][C:7]([N:3]4[CH2:4][CH2:5][CH2:6][C:2]4=[O:1])([CH2:14][CH:13]1[CH2:12]3)[CH2:8]2
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1CCCN1C12CC3CC(C1)C(C(=O)O)(C3)C2
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: NC12CC3CC1CC(N1CCCC1=O)(C3)C2
Temperature: 45 °C
Reaction time: 2 h
Yield: 56.7 %

Procedure:
To a stirred solution of the acid obtained in step II (0.5 g, 2.0 mmol) in CHCl3 (21 mL) at room temperature was added conc. H2SO4 (1.0 mL, 20 mmol) followed by NaN3 (0.39 g, 6.0 mmol) in portions over a period of 30 min., so that the temperature of the reaction did not rise above 40° C. The reaction was warmed to 45° C. and stirred for 2 h, then cooled to ice bath temperature, diluted with water and extracted with EtOAc. The aqueous layer was basified by adding 50% NaOH solution and extracted with CHCl3. The combined organic layer was washed with brine, dried over Na2SO4 and the solvent was removed under reduced pressure to obtain 1-(3-aminotricyclo[3.3.1.03,7]non-1-yl) pyrrolidin-2-one as an off-white solid (0.25 g) in 74% yield. m/z (M+1) 221; 1H NMR (CDCl3) 300 MHz δ 3.41 (t, J=7.0 Hz, 2H), 2.46 (dd, J=2.4, 10.3 Hz, 1H), 2.38-2.28 (m, 1H), 2.30 (t, J=8.3 Hz, 2H), 2.16-1.82 (m, 9H), 1.78 (dd J=2.6, 10.8 Hz, 1H), 1.66-1.58 (m, 1H), 1.51 (dd, J=2.5, 10.8 Hz, 1H).
Reaction SMILES: [C:1]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-])=O)(=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C]=O>[Pd].C(#N)C>[CH:2]([C:1]1[O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:18]=1)=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(C=Cc1ccccc1)Oc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Agent: [C]=O
Solvent: CC#N
Product: C(=Cc1nc2ccccc2o1)c1ccccc1
Temperature: 190 °C

Procedure:
An autoclave is charged with 13.45 g. o-nitrophenyl cinnamate, 2.5 g. 5% palladium-on-carbon, 0.40 g. ferric chloride and 90 ml. anhydrous acetonitrile, pressurized with carbon monoxide to 5000 psig., and heated at 190° C. for 6 hours. After the catalyst is removed by filtration, analysis of the reaction mixture by vapor phase chromatography shows that 2-styrylbenzoxazole is the major product. The 2-styrylbenzoxazole is isolated by chromatography on alumina using benzene as the eluent. After recrystallization from petroleum ether, it melts at 78°-79° C. and is identical with an authentic sample of 2-styrylbenzoxazole by mixed melting point, infrared spectrum and vapor phase chromatography.