Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[CH2:5]([N:7]([C:9]1[CH:10]=[C:11]([OH:17])[C:12](=[CH:15][CH:16]=1)[CH:13]=O)[CH3:8])[CH3:6]>>[CH2:5]([N:7]([C:9]1[CH:10]=[C:11]([OH:17])[C:12](=[CH:15][CH:16]=1)[CH:13]=[N:3][CH2:2][CH2:1][N:4]=[CH:13][C:12]1[C:11](=[CH:10][C:9]([N:7]([CH3:8])[CH2:5][CH3:6])=[CH:16][CH:15]=1)[OH:17])[CH3:8])[CH3:6]
Reactant: NCCN
Reactant: CCN(C)c1ccc(C=O)c(O)c1
Product: CCN(C)c1ccc(C=NCCN=Cc2ccc(N(C)CC)cc2O)c(O)c1
Temperature: 70 °C

Procedure:
A solution of 80 mg (1.33 mmol) of ethylenediamine is added dropwise, at room temperature, to a solution of 500 mg (2.79 mmol) of 4-(N-ethyl-N-methylamino)salicylaldehyde and the reaction solution is heated for 4 hours at 70° C. After cooling to room temperature, the precipitate formed is filtered off, washed with a small amount of cold ethanol and dried in a vacuum drying cabinet at 30° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH:21]2[CH2:26][CH2:25][N:24]([C:27](OC(C)(C)C)=O)[CH2:23][CH2:22]2)[C:10](=[O:20])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[OH:34][C:35]1[CH:42]=[CH:41][C:38](C=O)=[CH:37][CH:36]=1.[BH4-].C(OC(=O)C)(=O)C>C(O)C>[OH:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:27][N:24]2[CH2:23][CH2:22][CH:21]([N:9]([CH2:8][C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)[C:10](=[O:20])[CH2:11][C:12]3[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=3)[CH2:26][CH2:25]2)=[CH:37][CH:36]=1
Reactant: COc1ccc(CC(=O)N(Cc2ccc(C)cc2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: O=Cc1ccc(O)cc1
Agent: [BH4-]
Solvent: CC(=O)OC(C)=O
Solvent: CCO
Product: COc1ccc(CC(=O)N(Cc2ccc(C)cc2)C2CCN(Cc3ccc(O)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The product from example 13 above (20 mg, 0.06 mmol) was dissolved in abs. ethanol (2 ml). 4-Hydroxybenzaldehyde (139 mg, 1.1 mmol) was added followed by solid-supported borohydride (150 mg, 2.5 mmol/g resin; Aldrich 32,864-2). The mixture was shaken at room temperature. After 48 h, the resin was filtered off and acetic anhydride (0.02 ml, 0.2 mmol) was added to the organic solution. After 24 h, the mixture was concentrated and redissolved in methanol (2 ml). The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3×6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield: 19 mg; HRMS (FAB30, NBA) (M+H)+ 459.2655, C29H35N2O3 requires 459.2648; LC-MS: (M+H)+ 459.2, tr 2.84 min.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8](/[C:11](/[CH3:18])=[CH:12]/[C:13]([O:15]CC)=[O:14])=[CH:7][CH:6]=1.[OH-].[Na+]>CO>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8](/[C:11](/[CH3:18])=[CH:12]/[C:13]([OH:15])=[O:14])=[CH:7][CH:6]=1
Reactant: CCOC(=O)/C=C(\C)c1ccc(OCOC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCOc1ccc(/C(C)=C/C(=O)O)cc1
Yield: 70.1 %

Procedure:
A solution of ethyl (E)-3-[4-(methoxymethoxy)phenyl]-2-butenoate (3.79 g) in methanol was stirred with 0.76 mol/l aqueous sodium hydroxide at room temperature for 2 hours. Methanol was evaporated and 0.45 mol/l hydrochloric acid was added dropwise to the residue to precipitate a solid, which was then filtered, washed with water, and dried by heating under reduced pressure to give (E)-3-[4-(methoxymethoxy)phenyl]-2-butenoic acid (2.36 g, 70%) as a colorless solid.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]([C:17]3[N:18]=[CH:19][N:20](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:21]=3)=[O:16])[CH:11]=2)[CH:6]=1)=[O:4].[CH:41]([Mg]Br)=[CH2:42]>C1COCC1>[OH:16][C:15]([C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]=[C:5]([C:3]([NH:2][CH3:1])=[O:4])[CH:14]=[CH:13]2)([C:17]1[N:18]=[CH:19][NH:20][CH:21]=1)[CH2:41][CH3:42]
Reactant: CNC(=O)c1ccc2cc(C(=O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: CCC(O)(c1ccc2cc(C(=O)NC)ccc2c1)c1c[nH]cn1

Procedure:
The similar reaction as described in Example 50-(i) was carried out by using N-methyl-6-[(1-trityl-1H-imidazol-4-yl)carbonyl]-2-naphthamide (700 mg) and vinylmagnesium bromide in THF (1M; 5 mL) to give the titled compound (478 mg) as colorless powder.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[N:18]=[C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:16]3=[CH:25][C:26]([CH2:28][N:29]([CH3:31])[CH3:30])=[CH:27][N:15]3[N:14]=2)[CH:8]=1)(=O)=O.[NH3:32]>CO>[NH2:32][CH2:6][C:7]1[CH:8]=[C:9]([C:13]2[N:18]=[C:17]([N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[C:16]3=[CH:25][C:26]([CH2:28][N:29]([CH3:30])[CH3:31])=[CH:27][N:15]3[N:14]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: N
Reactant: CN(C)Cc1cc2c(N3CCOCC3)nc(-c3cccc(COS(C)(=O)=O)c3)nn2c1
Solvent: CO
Product: CN(C)Cc1cc2c(N3CCOCC3)nc(-c3cccc(CN)c3)nn2c1
Reaction time: 8 h
Yield: 56.2 %

Procedure:
Compound 19 (80 mg, 0.18 mmol) was added to 20 mL of saturated ammonia solution of methanol. The reaction was carried out at 80° C. in a sealed tube for 8 h. After the reaction mixture was concentrated, it was purified by a preparative plate (dichloromethane:methanol=6:1) to obtain 37 mg of colourless oil (56.2%). 1H NMR (300 MHz, CDCl3): δ 8.20 (s, 1H), 8.17-8.13 (m, 1H), 7.64 (s, 1H), 7.41-7.39 (m, 2H), 6.86 (s, 1H), 4.11 (t, J=4.7 Hz, 4H), 3.97 (s, 2H), 3.87 (t, J=4.7 Hz, 4H), 3.69 (s, 2H), 2.41 (s, 6H). LC-MS: 367 (M+1).
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].O=[C:7]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:8][NH:9][C:10]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11].Cl.O>CO>[NH2:5][C:3]([NH:2][N:1]=[C:7]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:8][NH:9][C:10]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])=[S:4]
Reactant: NNC(N)=S
Reactant: O=C(CNC(=O)C1CCCCC1)c1ccccc1
Agent: Cl
Solvent: CO
Solvent: O
Product: NC(=S)NN=C(CNC(=O)C1CCCCC1)c1ccccc1
Yield: 105.1 %

Procedure:
Thiosemicarbazide (2.23 g, 24.5 mmol) was added to a solution of cyclohexane carboxylic acid (2-oxo-2-phenyl-ethyl)-amide (6.0 g, 24.5 mmol), prepared in the previous step, in 87 ml of methanol plus 6.75 ml of 1N HCl plus 6.25 ml of water and the reaction stirred at room temperature for 4 days. The solvent was removed under reduced pressure to give 8.2 g of a green oil which was chromatographed on 400 g of silica gel (230-400 mesh) using ethyl acetate-methylene chloride as the eluent. The material isolated was recrystallized from isopropyl alcohol to give the title compound (3.55 g, 46%) as a white solid, mp 104-110° C.
Reaction SMILES: N[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9].N([O-])=O.[Na+].[OH-].[Na+].Cl.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([N+:26]([O-:28])=[O:27])=[C:23]([SH:25])[CH:24]=1>O>[N+:26]([C:22]1[CH:21]=[CH:20][C:19]([Cl:18])=[CH:24][C:23]=1[S:25][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9])([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1S
Reactant: Nc1cnccc1C(=O)O
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccncc1Sc1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 53 °C
Reaction time: 0.17 h
Yield: 95.3 %

Procedure:
A solution of 3-amino-4-carboxypyridine (1.4 g), sodium nitrite (0.81 g) and aqueous sodium hydroxide 2.9 M (13.3 ml) was added to a solution of aqueous hydrochloric acid 4.3 M (9.8 ml) while the temperature was maintained at 0-5 C. The mixture was stirred for 10 minutes and then added dropwise over the course of 2 hrs to a stirred mixture of 5-chloro-2-nitrothiophenol (2.34 g) and sodium hydroxide (2.63 g) in water (21 ml) maintained at about 53° C. (a brisk nitrogen evolution occurred). The mixture was stirred for 15 minutes, cooled to room temperature and filtered. The fitrate was made strongly acidic (pH=2) with hydrochloric acid 12 M and the precipitated solid was collected by filtration and dried to yield a brownish-orange solid (3 g). The solid was washed with dichloromethane:acetonitrile (30 ml) and dried to leave crude product (1.2 g). Crystallization from ethyl cellosolve led to the pure product, m.p. 280-281, °C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:38][CH:39]([F:41])[F:40])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26]C(C)(C)C)=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:37])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:38][CH:39]([F:41])[F:40])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:37])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CC(C)C)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1OC(F)F
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(C(CC(C)C)C(=O)Nc2ccc(C(=O)O)cc2)c(=O)cc1-c1cc(Cl)ccc1OC(F)F

Procedure:
263 mg (purity 88%, 0.39 mmol) of tert-butyl 4-[(2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-4-methylpentanoyl)amino]benzoate (racemate) were hydrolysed with TFA according to General Method 2. The crude product was purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 140 mg (67% of theory)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([O:9]C)=[C:4]([Cl:11])[N:3]=1.B(Br)(Br)Br>C(Cl)Cl.CO.O>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([OH:9])=[C:4]([Cl:11])[N:3]=1
Reactant: COc1c(Cl)nc(Cl)nc1Cl
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: Oc1c(Cl)nc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.4 %

Procedure:
Under an atmosphere of nitrogen a solution of 2,4,6-trichloro-5-methoxy-pyrimidine (4.0 g, 18.7 mmol) in DCM (200 mL) was cooled to 0° C. and treated with boron tribromide (neat, 6.6 mL, 65 mmol) dropwise. After stirring for 18 hours at room temperature LCMS analysis indicated complete reaction. The reaction mixture was cooled and diluted with methanol (25 mL, CARE, EXOTHERM!) and the reaction mixture diluted with water (200 mL). The aqueous layer was washed with DCM and the combined organic extracts dried (Na2SO4) filtered and concentrated in vacuo to give 2,4,6-trichloro-5-hydroxy-pyrimidine as a pale tan solid (2.55 g, 71%). 13C NMR (DMSO-d6): 149.23 (C), 145.25 (C), 145.08 (C). LCMS: RT=2.65/2.77 [M−H]−=197/199.
Reaction SMILES: O1CCCCC1[O:7][CH:8]([CH3:23])[C:9]#[C:10][C@H:11]1[CH2:15][CH2:14][C@H:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[O:12]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+].O>CO.[Cl-].[Na+].O>[OH:7][CH:8]([CH3:23])[C:9]#[C:10][C@H:11]1[CH2:15][CH2:14][C@H:13]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[O:12]1
Reactant: CC(C#C[C@H]1CC[C@H](c2ccc(F)cc2)O1)OC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: O
Solvent: CO
Product: CC(O)C#C[C@H]1CC[C@H](c2ccc(F)cc2)O1
Reaction time: 0.75 h
Yield: 100.6 %

Procedure:
trans-2-(3-Tetrahydropyranyloxy-but-1-ynyl)-5-(4-fluorophenyl)tetrahydrofuran (204, 280 mg, 0.9 mmol) was dissolved in methanol (15 mL). To this solution was added p-toluenesulfonic acid (50 mg) and the resulting solution was stirred for 45 minutes. Saturated sodium bicarbonate solution (10 mL) was added. After 5 minutes of stirring, the solution was added to 10 mL of water, diluted with 15 mL of brine and extracted with methylene chloride (3×30 mL). The combined organics were dried over sodium sulfate and the solvent was removed via rotary evaporator to yield 212 mg (100%) of trans-2-(3-hydroxy-but-1-ynyl)-5-(4-fluorophenyl) tetrahydrofuran (205). 1H-NMR (CDCl3) δ 7.29 (2H, dd, J=8.7, 5.2 Hz), 7.01 (2H, t, J=8.7 Hz), 5.09 (1H, t, J=7.4 Hz), 4.92 (1H, t, J=7.4 Hz), 4.59 (1H, q, J=6.6 Hz), 2.30-2.50 (2H, m), 2.05-2.15 (1H, m), 2.00 (1H, br s), 1.75-1.88 (1H, m), 1.47 (3H, d, J=6.6 Hz).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].[O:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]([NH:32][C@@H:33]([CH3:37])[C:34](O)=[O:35])=[O:31])[CH2:25][CH2:24]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O.CCOC(C)=O>[CH2:16]([O:15][C:10]1[CH:9]=[C:8]([CH2:7][C@H:2]([NH:1][C:34](=[O:35])[C@@H:33]([NH:32][C:30](=[O:31])[CH2:29][N:26]2[CH2:27][CH2:28][O:23][CH2:24][CH2:25]2)[CH3:37])[C:3]([O:5][CH3:6])=[O:4])[CH:13]=[CH:12][C:11]=1[CH3:14])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C[C@H](NC(=O)CN1CCOCC1)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(C)c(OCc2ccccc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccc(C)c(OCc2ccccc2)c1)NC(=O)[C@H](C)NC(=O)CN1CCOCC1
Temperature: 25 °C
Yield: 96.5 %

Procedure:
Crude (S)-methyl 2-amino-3-(3-(benzyloxy)-4-methylphenyl)propanoate (TFA salt, 2.5 mmol) was dissolved in DMF (5 mL) and (S)-2-(2-morpholinoacetamido)propanoic acid (0.65 g, 3.0 mmol), HATU (1.43 g, 3.70 mmol), and DIEA (1.0 mL) were added at 0° C. with stirring. The reaction mixture was allowed to warm to ambient temperature and stirred for 3 h. EtOAc (100 mL) and water (100 mL) was added. The aqueous phase was extracted with EtOAc (30 mL×3) and the combined organic phases were washed with brine (50 mL×3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (DCM/MeOH=20:1) to afford (S)-Methyl 3-(3-(benzyloxy)-4-methylphenyl)-2-((S)-2-(2-morpholinoacetamido) propanamido)propanoate (1.2 g, 96% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[CH2:9][OH:10])=[CH:4][CH:3]=1.CS(O[C@@H:18]([C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1)[CH2:19][CH2:20][C@@H:21](OS(C)(=O)=O)[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)(=O)=O.C(OCC)(=O)C.CCCCCC>CN(C=O)C>[N+:28]([C:25]1[CH:26]=[CH:27][C:22]([C@@H:21]2[CH2:20][CH2:19][C@@H:18]([C:36]3[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=3)[N:1]2[C:2]2[CH:3]=[CH:4][C:5]([C:8]([CH3:12])([CH3:11])[CH2:9][OH:10])=[CH:6][CH:7]=2)=[CH:23][CH:24]=1)([O-:30])=[O:29]
Reactant: CS(=O)(=O)O[C@H](CC[C@@H](OS(C)(=O)=O)c1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(CO)c1ccc(N)cc1
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(CO)c1ccc(N2[C@H](c3ccc([N+](=O)[O-])cc3)CC[C@H]2c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 50 °C
Yield: 34.1 %

Procedure:
The product from Example 194C (0.595 g, 3.60 mmole) was combined in DMF (3 mL) with (1R,4R)-1,4-bis(4-nitrophenyl)butane-1,4-diyl dimethanesulfonate (0.259 g, 0.530 mmole), prepared as described in Example 37C, then heated overnight under nitrogen in an oil bath at 50° C. The reaction mixture was partitioned between ethyl acetate (50 mL) and water (50 mL). The organic phase was water washed (3×25 mL), dried over MgSO4, filtered and concentrated to an oil. Chromatography on silica gel eluting with ethyl acetate-hexane provided the title compound (0.0835 g, 34.1% yield) as an orange semi-solid.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH2:9][CH3:10])[CH:3]=1.[CH3:11][N:12]1[CH:16]=[C:15](B2OC(C)(C)C(C)(C)O2)[CH:14]=[N:13]1>>[CH2:9]([C:4]1[CH:3]=[C:2]([C:15]2[CH:14]=[N:13][N:12]([CH3:11])[CH:16]=2)[CH:8]=[CH:7][C:5]=1[NH2:6])[CH3:10]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CCc1cc(Br)ccc1N
Product: CCc1cc(-c2cnn(C)c2)ccc1N

Procedure:
The title compound was prepared according to the method described for Preparation 98 using 4-bromo-2-ethylaniline and 1-methylpyrazole-4-boronic acid pinacol ester.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31]([N:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)=[O:32])[CH2:25]4)[N:18]=[N:19][C:20]=3[C:21]([NH2:23])=[O:22])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[C:48](Cl)(=[O:51])[CH2:49][CH3:50]>CN(C=O)C>[N:33]1([C:31]([NH:30][C@@H:26]2[CH2:27][CH2:28][CH2:29][N:24]([C:17]3[N:18]=[N:19][C:20]([C:21]([NH2:23])=[O:22])=[C:15]([NH:14][C:11]4[CH:12]=[CH:13][C:8]([CH:5]5[CH2:6][CH2:7][N:2]([C:48](=[O:51])[CH2:49][CH3:50])[CH2:3][CH2:4]5)=[CH:9][CH:10]=4)[N:16]=3)[CH2:25]2)=[O:32])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: NC(=O)c1nnc(N2CCC[C@@H](NC(=O)N3CCCCC3)C2)nc1Nc1ccc(C2CCNCC2)cc1
Reactant: CCC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC(=O)N1CCC(c2ccc(Nc3nc(N4CCC[C@@H](NC(=O)N5CCCCC5)C4)nnc3C(N)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(R)-5-(4-(Piperidin-4-yl)phenylamino)-3-(3-(piperidine-1-carboxamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide hydrochloride (494) (70 mg, 0.13 mmol) was dissolved in 4 mL DMF. To it were added DIEA (230 μL, 1.30 mmol) and then propionyl chloride (36 μL, 0.39 mmol). The mixture was stirred at RT for 1 hour, quenched with 0.3 mL TFA, and directly subjected to reverse phase prep HPLC to isolate the title compound, (R)-3-(3-(piperidine-1-carboxamido)piperidin-1-yl)-5-(4-(1-propionylpiperidin-4-yl)phenylamino)-1,2,4-triazine-6-carboxamide (498), as HCl salt (45 mg). LC-MS (ESI): m/z (M+1) 564.3. UV: λ=263, 329, 338 nm.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=[O:6].C(N(C(C)C)C(C)C)C.[CH3:20][C:21]1[O:25][N:24]=[C:23]([C:26](Cl)=[O:27])[CH:22]=1>C(Cl)Cl.CCOC(C)=O>[Cl:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[NH:1][C:26]([C:23]1[CH:22]=[C:21]([CH3:20])[O:25][N:24]=1)=[O:27]
Reactant: Cc1cc(C(=O)Cl)no1
Reactant: Nc1cc(C=O)ccc1Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C(=O)Nc2cc(C=O)ccc2Cl)no1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 25.7 %

Procedure:
To a solution of 3-amino-4-chlorobenzaldehyde 2 (0.267 g, 1.72 mmol) in DCM (5 mL) at 0° C. was added N-ethyl-N-isopropylpropan-2-amine (0.600 mL, 3.44 mmol) and 5-methylisoxazole-3-carbonyl chloride (0.292 g, 2.01 mmol). The reaction mixture was stirred at 0° C. for 30 min, warmed to room temperature, stirred for 1 h, and diluted with EtOAc. The organic phase was washed with saturated NaHCO3 (1×), brine (1×), dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel (eluted with 15% to 50% EtOAc in hexanes) gave N-(2-chloro-5-formylphenyl)-5-methylisoxazole-3-carboxamide 3 (0.117 g, 25.8% yield) as a white solid. Mass spectrum: calculated for C12H9ClN2O3 264.0. found 265.0 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[CH3:10].C(Cl)Cl.[OH2:14]>CC#N>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[CH:10]=[O:14]
Reactant: O
Reactant: COc1cccc(C)c1C
Solvent: CC#N
Solvent: ClCCl
Product: COc1cccc(C)c1C=O
Temperature: 25 °C

Procedure:
A mixture of commercially available 1-methoxy-2,3-dimethylbenzene (10.000 g; 73.40 mmol), copper(II) sulfate pentahydrate CuSO4.5H2O (18.334 g; 73.40 mmol), and potassium peroxodisulfate K2S2O8 (59.547 g; 220.00 mmol) in MeCN (250 ml) and water (250 ml) was heated at reflux, under nitrogen, for 30 min. After cooling to rt, DCM was added and the aq. layer was further extracted with DCM. The mixed organic layers were dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (heptane/AcOEt=9/1) afforded 2-methoxy-6-methylbenzaldehyde as a yellow oil. LC-MS (conditions A): tR=0.70 min.; no ionisation.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][C:14]=1[F:15])[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1)[C:10]1[CH2:9][CH2:8][CH:7]([NH:24][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[CH2:6][C:5]2=1.BrC1C(F)=C2C(=CC=1)[N:40](CC1C=CC=C(F)C=1)[C:39]1CCC(NC(=O)C(C)C)CC2=1.[Cu]C#N.C(N)CN>CN1CCCC1=O.CCOC(C)=O.O.[Cu]I>[C:39]([C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][C:14]=1[F:15])[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1)[C:10]1[CH2:9][CH2:8][CH:7]([NH:24][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[CH2:6][C:5]2=1)#[N:40]
Reactant: CC(C)C(=O)NC1CCc2c(c3cc(Br)c(F)cc3n2Cc2cccc(F)c2)C1
Reactant: CC(C)C(=O)NC1CCc2c(c3c(F)c(Br)ccc3n2Cc2cccc(F)c2)C1
Agent: N#C[Cu]
Agent: [Cu]I
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)C(=O)NC1CCc2c(c3cc(C#N)c(F)cc3n2Cc2cccc(F)c2)C1
Temperature: 130 °C
Yield: 20 %

Procedure:
Dissolve a 65:35 mixture of N-[6-bromo-7-fluoro-9-(3-fluoro-benzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-isobutyramide and N-[6-bromo-5-fluoro-9-(3-fluoro-benzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-isobutyramide (500 mg, 1.08 mmol; Preparation 20) in N-methylpyrrolidinone (10 mL). Sparge the resulting solution with nitrogen for 30 min, then add copper(I) cyanide (291 mg, 3.25 mmol) and copper(I) iodide (619 mg, 3.25 mmol). Heat to 130° C. for three days, then cool to room temperature. Dilute the reaction mixture with EtOAc (200 mL) and water (100 mL). Add ethylene diamine until all the solids are dissolved (about 20 mL). Separate the layers, then wash the organic layer with water (3×75 mL). Dry the organic portion (MgSO4), filter, and concentrate the organic layer to afford 474 mg of crude product. Separate the title compound from this mixture by silica gel chromatography (0-10% EtOAc/CHCl3), affording the title compound as a white solid in 20% yield. MS (ES): m/z 408 (M+1), 406 (M−1); HPLC: Rt=2.51 min, (96%).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[Br:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](Cl)=[N:13][OH:14])=[C:8]([F:16])[CH:7]=1>CCOCC>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[N:13][OH:14])[NH:4][CH:1]2[CH2:3][CH2:2]2)=[C:8]([F:16])[CH:7]=1
Reactant: ON=C(Cl)c1ccc(Br)cc1F
Reactant: NC1CC1
Solvent: CCOCC
Product: ON=C(NC1CC1)c1ccc(Br)cc1F
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Cyclopropylamine (1.6 ml) was added dropwise to an ice-old solution of 4-bromo-2-fluoro-N-hydroxybenzenecarboximidoyl chloride (Intermediate 51) (0.59 g) in dry ether (25 ml) under nitrogen. After the addition the mixture was allowed to warm to room temp. then stirred for 18 h. The resulting precipitate was collected by filtration then purified by column chromatography on silica eluting with cyclohexane:ethyl acetate (3:2) to give the title compound as a white solid (0.435 g).
Reaction SMILES: C(OC([C:6]([C:20]([O:22]CC)=[O:21])([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])[CH2:7][C:8]([OH:10])=O)=O)C.C(Cl)(=O)C(Cl)=O.O.Cl>C(Cl)Cl>[CH3:19][C:14]1[C:13]2[CH2:12][CH2:11][CH:6]([C:20]([OH:22])=[O:21])[CH2:7][C:8](=[O:10])[C:18]=2[CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)C(CCc1ccccc1C)(CC(=O)O)C(=O)OCC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Product: Cc1cccc2c1CCC(C(=O)O)CC2=O
Temperature: 5 °C
Reaction time: 8 h
Yield: 54.2 %

Procedure:
16.8 g (0.0499 mol) of 3,3-bis-ethoxycarbonyl-5-o-tolyl-pentanoic acid were dissolved in 120 mL of CH2Cl2 under a nitrogen atmosphere. The solution was cooled to 5° C. and 19 mL (0.1498 mol) of oxalyl chloride were added dropwise. After 3 h the volatiles were removed in vacuo, the resulting oil was dissolved in 200 mL of CH2Cl2 and this solution was added dropwise, at 0° C. and under inert atmosphere, to a suspension of 26.6 g (0.1996 mol) of AlC3 in 300 mL of CH2Cl2. The resulting suspension was vigorously stirred overnight, during which time it was allowed to warm to room temperature. Water was added, followed by 1N HCl up to pH 1. The layers were separated, the organic phase was dried and the solvent was removed in vacuo. The resulting crude product was taken up in dioxane (60 mL) and 6N HCl (200 mL) and heated to reflux for 6 h. After cooling, water was added and the reaction mixture was extracted with Et2O. The organic phase was dried, the solvent was removed in vacuo and the resulting crude product was purified by flash chromatography eluting with Et2O, yielding 5.9 g of compound which was triturated in (i-Pr)2O, filtered and dried, yielding 4.33 g of the title product.