Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]([C@H:24]1[CH2:27][C@@H:26]([C:28]([O:30]C)=[O:29])[CH2:25]1)([CH2:9][C:10]1[C:11]2[C:16]([CH:17]=[C:18]3[C:23]=1[CH:22]=[CH:21][CH:20]=[CH:19]3)=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]([O:7]C)=[O:6])=C=O.[OH-].[Na+]>>[NH2:1][C:4]([C@H:24]1[CH2:27][C@@H:26]([C:28]([OH:30])=[O:29])[CH2:25]1)([CH2:9][C:10]1[C:11]2[C:16]([CH:17]=[C:18]3[C:23]=1[CH:22]=[CH:21][CH:20]=[CH:19]3)=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)C(Cc1c2ccccc2cc2ccccc12)(N=C=O)[C@H]1C[C@@H](C(=O)OC)C1
Agent: [Na+]
Agent: [OH-]
Product: NC(Cc1c2ccccc2cc2ccccc12)(C(=O)O)[C@H]1C[C@@H](C(=O)O)C1

Procedure:
Methyl cis-2-isocyanato-2-(3-methoxycarbonyl cyclobutyl)-3-(9-anthracenyl)propanoate (65 mg, 0.16 mmol) was treated with aqueous sodium hydroxide and the reaction worked up following the procedure described in Example 16 (vi) to give the title compound as a pale yellow solid (m.p. 213-216° C.), 1H NMR (D2 0/NaOD) δ 8.42(s), 8.35(d), 8.06(s), 8.02(d),7.50-7.58 (m), 3.87 (dd), 2.70-2.92 (m), 1.88-2.06(m)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:31]([CH3:32])=[N:30][NH:29][C:5]2=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[N:13]([C:21]3[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=3)[N:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1)[O:8][C:7]2=[O:28].C(#N)C.O.[CH:37]([NH2:40])([CH3:39])[CH3:38]>[Cl-].[Na+].O>[CH:37]([NH:40][C:7]([C:6]1[C:11]([NH:10][C:9]([C:12]2[N:13]([C:21]3[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=3)[N:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=2)=[O:8])=[C:2]([Cl:1])[CH:3]=[C:4]2[C:5]=1[NH:29][N:30]=[C:31]2[CH3:32])=[O:28])([CH3:39])[CH3:38]
Reactant: Cc1n[nH]c2c1cc(Cl)c1nc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)oc(=O)c12
Reactant: CC(C)N
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1n[nH]c2c(C(=O)NC(C)C)c(NC(=O)c3cc(C(F)(F)F)nn3-c3ncccc3Cl)c(Cl)cc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 27.8 %

Procedure:
To a suspension of 148 mg (0.20 mmol) of the above 5-chloro-7-[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-3-methyl-1H-8-oxa-1,2,6-triaza-cyclopenta[a]naphthalen-9-one in 5.92 mL of a mixture acetonitrile: H2O 4:1 (v/v) is added 51 μL (0.60 mmol) of isopropylamine. The reaction mixture is stirred for 6 hours at ambient temperature. Brine is then added to the mixture and the product is extracted with ethyl acetate (3 times). The regrouped organic phases are dried on Na2SO4, filtrated and evaporated. The purification of the residue by flash chromatography (SiO2, heptane/ethyl acetate 1:1) affords 30 mg (28%) of a white solid; LC/MS:540/542 (M+H)+, m.p.: 235-236° C.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=O.[NH2:15][NH2:16]>>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[NH:16][N:15]=[C:3]([OH:2])[CH:4]=2)=[CH:8][CH:9]=1
Reactant: NN
Reactant: COC(=O)CC(=O)c1ccc(F)cc1
Product: Oc1cc(-c2ccc(F)cc2)[nH]n1
Yield: 84.4 %

Procedure:
5-(4-Fluoro-phenyl)-1H-pyrazol-3-ol (7.67 g, 84%) was prepared as a white solid from 3-(4-Fluoro-phenyl)-3-oxo-propionic acid methyl ester (10.0 g, 51.0 mmol) and hydrazine (4.76 mL, 153 mmol) by a procedure analogous to Example 22. C9H7FN2O: 1H NMR (d6-DMSO): δ 7.66 (dd, 2H, JCH—CF=11.7 Hz, JCH—CH=8.7 Hz), 7.21 (d, 2H, J=8.7 Hz), 5.83 (s, 1H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:11](O)=[O:12])[C:7](=[O:21])[CH:6]=1.[CH3:27][O:28][C:29](=[O:37])[C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[N:32][CH:31]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)C(C)C)(C)C>ClCCl.C(OCC)(=O)C>[CH3:27][O:28][C:29](=[O:37])[C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:11](=[O:12])[C@@H:10]([N:8]2[CH2:9][C:5]([O:4][C:3]3[C:22]([F:26])=[CH:23][CH:24]=[CH:25][C:2]=3[Cl:1])=[CH:6][C:7]2=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[N:32][CH:31]=1
Reactant: COC(=O)c1ccc(N)nc1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1CC(Oc2c(F)cccc2Cl)=CC1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC(Oc3c(F)cccc3Cl)=CC2=O)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 32.3 %

Procedure:
A solution of (S)-2-[4-(2-chloro-6-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionic acid (prepared as in Example 67, 206 mg, 0.54 mmol) in dichloromethane (5 mL) was treated with 6-amino-nicotinic acid methyl ester (110 mg, 0.72 mmol), bromotripyrrolidinophosphonium hexafluorophosphate (503 mg, 1.1 mmol) and N,N-diisopropylethylamine (150 mg, 1.1 mmol). The reaction mixture was stirred for 4 h at 25° C., under nitrogen. The reaction mixture was diluted with ethyl acetate, washed with saturated ammonium chloride, water, a saturated sodium chloride solution and dried over sodium sulfate. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g, 0% to 100% ethyl acetate/hexanes) to afford 6-{(S)-2-[4-(2-chloro-6-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionylamino}-nicotinic acid methyl ester (90 mg, 33%): 1H NMR (300 MHz, DMSO-d6) δ ppm 0.77-1.36 (m, 6H) 1.40-1.92 (m, 7H) 3.86 (s, 3H) 4.29 (d, J=18.7 Hz, 1H) 4.64 (d, J=18.7 Hz, 1H) 5.00 (s, 1H) 5.01-5.10 (m, 1H) 7.30-7.61 (m, 3H) 8.16 (d, J=8.8 Hz, 1H) 8.29 (dd, J=8.8, 2.1 Hz, 1H) 8.87 (d, J=2.1 Hz, 1H) 11.32 (s, 1H). HR-ES-MS m/z calculated for C26H27ClFN3O5 [M+H]+ 516.1696, observed 516.1696.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(N(CC)CC)C.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24](Cl)=O>C1(C)C=CC=CC=1>[CH3:11][C:8]1[CH:9]=[CH:10][C:2]2[N:1]=[C:24]([C:20]3[S:19][CH:23]=[CH:22][CH:21]=3)[O:5][C:4](=[O:6])[C:3]=2[CH:7]=1
Reactant: O=C(Cl)c1cccs1
Reactant: Cc1ccc(N)c(C(=O)O)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc2nc(-c3cccs3)oc(=O)c2c1
Temperature: 25 °C

Procedure:
2-Amino-5-methylbenzoic acid (0.5 g) and triethyl amine (10 ml) were mixed in dry toluene (20 ml). 2-Thienylcarbonyl chloride (1.07 g) was added dropwise under cooling and stirring. The mixture was subsequently heated to RT for 24 h, then heated to 80° C. for 1 h. After cooling on ice the precipitate was filtered off and the filtrate evaporated to dryness. The residue was partitioned between methylene chloride and potassium carbonate (2N), the organic layers separated, dried over magnesium sulfate and evaporated to dryness. The raw product was purified by column chromatography on silicagel using heptane/ethyl acetate as eluent.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH2:15](N)[CH:16]([CH3:18])[CH3:17].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:15]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[CH:16]([CH3:18])[CH3:17]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: CC(C)CN
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)Cc1c([N+](=O)[O-])cnc2ccccc12

Procedure:
4-chloro-3-nitro-quinoline is reacted with isobutyl amine in the presence of triethylamine (TEA) at between −10 and +15° C. in toluene, while excluding moisture. After washing and phase separation, the organic solution is ready for the next step.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[N:18]([S:21]([C:24]5[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=5)(=[O:23])=[O:22])[CH:19]=[CH:20][C:13]=34)=[C:9]([CH3:11])[N:10]=2)[N:7]=1.[CH3:31][C@@H:32]1[CH2:37][NH:36][CH2:35][CH2:34][NH:33]1.C(N(CC)CC)C>C(O)CCCC.Cl>[CH3:11][C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([N:36]3[CH2:35][CH2:34][NH:33][C@H:32]([CH3:31])[CH2:37]3)=[N:7][N:6]2[C:8]=1[C:12]1[CH:17]=[CH:16][N:15]=[C:14]2[N:18]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH:19]=[CH:20][C:13]=12
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4c(C)nc5ccc(Cl)nn45)ccnc32)cc1
Reactant: C[C@@H]1CNCCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCCO
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4c(C)nc5ccc(N6CCN[C@H](C)C6)nn45)ccnc32)cc1
Temperature: 150 °C
Yield: 60.2 %

Procedure:
A mixture of 0.325 g (0.97 mmol) of 6-chloro-2-methyl-3-{1-[(4-methylphenyl)sulphonyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}imidazo[1,2-b]pyridazine, 0.15 g (1.5 mmol) of (2R)-2-methylpiperazine and 0.10 ml (0.74 mmol) of triethylamine in 5 ml of pentanol is heated under reflux for 3 days at 150° C. The reaction medium is diluted with 100 ml of a 1N aqueous solution of hydrochloric acid and the solution is washed with ethyl acetate. The aqueous phase is then basified by addition of aqueous ammonia and the product is extracted with dichloromethane. The organic phase is separated, dried over sodium sulphate and the solvent is removed by evaporation under reduced pressure. The chestnut brown oil obtained is then chromatographed over a silica gel column (35 g) by eluting with a mixture of dichloromethane, methanol and aqueous ammonia (90/10/1) in order to give 0.293 g of 2-methyl-6-[(3R)-3-methylpiperazin-1-yl]-3-{1-[(4-methylphenyl)sulphonyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}imidazo[1,2-b]pyridazine in the form of a yellow oil after drying.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]1[CH:16]=[N:15][CH:14]=[CH:13][C:9]=1[C:10](O)=[O:11]>C1COCC1>[F:7][C:8]1[CH:16]=[N:15][CH:14]=[CH:13][C:9]=1[CH2:10][OH:11]
Reactant: O=C(O)c1ccncc1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccncc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 46.5 %

Procedure:
At 0° C. LAH (200 mg, 4 eq.) was added to 3-fluoro-isonicotinic acid (186 mg, 1.32 mmol, 1 eq.) suspension in 25 mL THF. The reaction was stirred at 0° C. for 1 hour. The reaction was quenched by adding 0.2 mL water, followed by 0.4 mL 10% NaOH aqueous solution and 0.6 mL water at 0° C. Ethyl acetate was added to the reaction crude and washed with brine. n-Butanol was used to extract back from the brine. The organic layers were combined and concentrated down and purified (silica gel, 0-15% MeOH/DCM) to give colorless oil (78 mg, 46%). 1H NMR (300 MHz, CD3OD): δ 8.39 (m, 2H), 7.61 (m, 1H), 4.86 (s, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][C:4]([C:6]1(O)[C:15]2[CH:14]=[N:13][C:12]([O:16][CH3:17])=[CH:11][C:10]=2[CH2:9][CH2:8][CH2:7]1)=[CH2:5].S(=O)(=O)(O)O.N>O>[CH3:19][N:2]([CH3:1])[CH2:3][C:4]([C:6]1[C:15]2[CH:14]=[N:13][C:12]([O:16][CH3:17])=[CH:11][C:10]=2[CH2:9][CH2:8][CH:7]=1)=[CH2:5]
Reactant: C=C(CN(C)C)C1(O)CCCc2cc(OC)ncc21
Agent: N
Agent: O=S(=O)(O)O
Solvent: O
Product: C=C(CN(C)C)C1=CCCc2cc(OC)ncc21
Reaction time: 0.5 h

Procedure:
A solution of 0.04 part of N,N-dimethyl-N-(2-[5,6,7,8-tetrahydro-8-hydroxy-3-methoxyisoquinol-8-yl]prop-2-en-1-yl)amine and 0.5 part by volume of concentrated sulfuric acid is allowed to stand at room temperature for about 30 minutes. Then the reaction mixture is added to water and basified with aqueous ammonia. The solution is extracted with ether and the ethereal extracts are washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated under reduced pressure to yield N,N-dimethyl-N-(2-[5,6-dihydro-3-methoxyisoquinol-8-yl]prop-2-en-1-yl)amine, identical to the product of Example 16A.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]2[N:13]([CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:12]([CH3:20])=[N:11][CH:10]=2)=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1.Br[C:22]1[C:34]([F:35])=[CH:33][C:25]([CH2:26][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[C:24]([F:36])[CH:23]=1.CCC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>[F:35][C:34]1[CH:33]=[C:25]([CH2:26][N:27]2[CH2:28][CH2:29][O:30][CH2:31][CH2:32]2)[C:24]([F:36])=[CH:23][C:22]=1[NH:8][C:5]1[N:4]=[C:3]([C:9]2[N:13]([CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:12]([CH3:20])=[N:11][CH:10]=2)[C:2]([F:1])=[CH:7][N:6]=1
Reactant: Cc1ncc(-c2nc(N)ncc2F)n1C1CCOCC1
Reactant: Fc1cc(CN2CCOCC2)c(F)cc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: Cc1ncc(-c2nc(Nc3cc(F)c(CN4CCOCC4)cc3F)ncc2F)n1C1CCOCC1
Temperature: 110 °C
Reaction time: 8 h
Yield: 64.3 %

Procedure:
5-Fluoro-4-(2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)pyrimidin-2-amine (0.876 g, 3.16 mmol), 4-(4-bromo-2,5-difluorobenzyl)morpholine (0.923 g, 3.16 mmol), Sodium tert-pentoxide (0.696 g, 6.32 mmol, (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (0.026 g, 0.03 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.018 g, 0.03 mmol) in toluene (10 mL) were mixed and degassed. The mixture was stirred at 110° C. under a nitrogen atmosphere overnight. The mixture was concentrated. Dichloromethane and water was added and the phases were separated. The organic phase was concentrated and the crude was purified by prep HPLC. The pooled fractions were concentrated to about half volume and the residue was extracted with EtOAc (×2). The organic phases were concentrated and the residue was dried under vacuum at 40° C. over a weekend to give the title compound (0.992 g, 64%) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:23]=[C:22]2[C:5]([CH2:6][C:7]3([C:15]42[NH:19][C:18](=S)[C:17]([CH3:21])=[N:16]4)[CH2:12][CH2:11][CH:10]([O:13][CH3:14])[CH2:9][CH2:8]3)=[CH:4][CH:3]=1.[NH3:24]>>[Br:1][C:2]1[CH:23]=[C:22]2[C:5]([CH2:6][C:7]3([C:15]42[N:19]=[C:18]([NH2:24])[C:17]([CH3:21])=[N:16]4)[CH2:12][CH2:11][CH:10]([O:13][CH3:14])[CH2:9][CH2:8]3)=[CH:4][CH:3]=1
Reactant: COC1CCC2(CC1)Cc1ccc(Br)cc1C21N=C(C)C(=S)N1
Reactant: N
Product: COC1CCC2(CC1)Cc1ccc(Br)cc1C21N=C(C)C(N)=N1
Temperature: 120 °C
Yield: 82.2 %

Procedure:
6′-Bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-4″(3″H)-thione (Example 19 Step 3, 0.936 g, 2.38 mmol) was taken up in ammonia (7M in MeOH, 10 mL, 70.00 mmol) and the resulting mixture was bubbled with argon and then heated in the microwave reactor at 120° C. for 1 h. The solvent was evaporated. Ammonia (7M in MeOH, 6 mL, 42 mmol) was added and the reaction was bubbled with argon and heated again using MW for 60 min at 120° C. The solvent was evaporated and ammonia (7M in MeOH, 10 mL, 70 mmol) was added. The reaction was bubbled with argon and then heated using MW for 2 h at 120° C. The solvent was evaporated and ammonia (7M in MeOH, 15 mL, 105 mmol) was added and the reaction was heated again for 2 h at 120° C. The solvent was evaporated and ammonia (7M in MeOH, 15 mL, 105 mmol) was added and the reaction was heated again for 2 h at 120° C. The solvent was evaporated and ammonia (7M in MeOH, 20 mL, 140 mmol) was added. The reaction was heated again using MW for 1 h at 120° C. The solvent was evaporated and the resulting residue was taken up in DCM (60 mL) and brine (×2) and poured into a phase separator. The organic phase was dried with MgSO4, filtered and evaporated to give the title compound (0.736 g, 82% yield) as a mixture of isomers: 1H NMR (500 MHz, CDCl3) δ ppm 1.09 (td, 1H), 1.27-1.49 (m, 3H), 1.62-1.74 (m, 2H), 1.93-2.01 (m, 2H), 2.37 (s, 3H), 3.04-3.18 (m, 3H), 3.34 (s, 3H), 6.90 (d, 1H), 7.20 (d, 1H), 7.38 (dd, 1H); MS (MM-ES+APCI)+m/z 376 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:4][CH:3]=1.[C:13]1([CH:19]([C:25]2[C:26](=[O:35])[C:27]([CH3:34])=[C:28]([CH3:33])[C:29](=[O:32])[C:30]=2[CH3:31])[CH2:20][CH2:21][C:22](O)=[O:23])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C.C(N(CC)CC)C>[N:8]1([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:22](=[O:23])[CH2:21][CH2:20][CH:19]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:25]3[C:26](=[O:35])[C:27]([CH3:34])=[C:28]([CH3:33])[C:29](=[O:32])[C:30]=3[CH3:31])=[CH:7][CH:6]=2)[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: CC1=C(C)C(=O)C(C(CCC(=O)O)c2ccccc2)=C(C)C1=O
Reactant: Nc1ccc(-n2ccnc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1=C(C)C(=O)C(C(CCC(=O)Nc2ccc(-n3ccnc3)cc2)c2ccccc2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 45.2 %

Procedure:
To a solution of 1-(4-aminophenyl)imidazole(0.71 g), 4-phenyl 4-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)butanoic acid(1.25 g), ,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(0.85 g) and 1-hydroxybenzotriazole(0.85g) in DMF(8 ml) was added triethylamine(0.7 ml) and the mixture was stirred at room temperature for 20 hours. The reaction mixture was poured into ice water and the precipitate was filtered and dissolved in chloroform-methanol. This solution was washed with brine, dried (MgSO4) and evaporated to dryness. The residue was purified by column chromatography on silica gel (chloroform: methanol=100:3) to obtain the title compound (0.82 g, amorphous).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=O)[CH:4]([CH2:9][C:10]([C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=3[N:13]=2)=O)[CH2:3]1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=1>>[CH3:1][CH:2]1[CH2:7][CH2:6][C:5]2[N:22]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)[C:10]([C:12]3[N:16]([CH3:17])[C:15]4[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=4[N:13]=3)=[CH:9][C:4]=2[CH2:3]1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: CC1CCC(=O)C(CC(=O)c2nc3ccccc3n2C)C1
Product: CC1CCc2c(cc(-c3nc4ccccc4n3C)n2-c2ccc(C(=O)O)cc2)C1
Yield: 60 %

Procedure:
Following the general methods as outlined under Intermediate 13, starting from 4-methyl-2-[2-(1-methyl-1H-benzimidazol-2-yl)-2-oxoethyl]cyclohexanone and 4-aminobenzoic acid, the title compound was isolated in 60% yield (98% purity by HPLC). MS(ESI+): 386.6; MS(ESI−): 384.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][CH2:5][NH:6][C:7](=[O:33])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:19][C:20]2[CH:25]=[CH:24][C:23](Br)=[C:22]([CH:27]3[O:32][CH2:31][CH2:30][CH2:29][O:28]3)[CH:21]=2)[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:10][CH:9]=1.[F-].[K+].[CH:37]([C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1)([CH3:39])[CH3:38]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:34])[CH2:4][CH2:5][NH:6][C:7](=[O:33])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:19][C:20]2[CH:25]=[CH:24][C:23]([C:43]3[CH:44]=[CH:45][C:40]([CH:37]([CH3:39])[CH3:38])=[CH:41][CH:42]=3)=[C:22]([CH:27]3[O:32][CH2:31][CH2:30][CH2:29][O:28]3)[CH:21]=2)[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:10][CH:9]=1
Reactant: COC(=O)CCNC(=O)c1ccc(C(CC(C)C)Oc2ccc(Br)c(C3OCCCO3)c2)cc1
Reactant: CC(C)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Product: COC(=O)CCNC(=O)c1ccc(C(CC(C)C)Oc2ccc(-c3ccc(C(C)C)cc3)c(C3OCCCO3)c2)cc1
Yield: 94.6 %

Procedure:
3-{4-[1-(4-Bromo-3-[1,3]dioxan-2-yl-phenoxy)-3-methyl-butyl]-benzoylamino}-propionic acid methyl ester (560 mg, 1.05 mmol), potassium Fluoride (183 mg, 3.15 mmol), 4-isopropylphenyl boronic acid (344 mg, 2.1 mmol) and tetrakis(triphenylphosphine)palladium (121 mg, 0.105 mmol) are placed in a flask. After the reaction is purged with N2 for several times, THF/H2O (20 ml/5 ml) is added. The resulting solution is refluxed overnight, loaded on silica gel, eluted with hexane and ethyl acetate to give the titled compound (570 mg).
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.CC1C=CC(S([N:24]=[C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][N:26]2[CH:34]([CH3:44])[C:35](=O)[CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])(=O)=O)=CC=1>ClCCl>[CH3:44][C:34]1[N:26]2[CH:27]=[C:28]([N+:31]([O-:33])=[O:32])[CH:29]=[CH:30][C:25]2=[N:24][C:35]=1[CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]
Reactant: CCOC(=O)CCC(=O)C(C)n1cc([N+](=O)[O-])ccc1=NS(=O)(=O)c1ccc(C)cc1
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCOC(=O)CCc1nc2ccc([N+](=O)[O-])cn2c1C
Temperature: 40 °C
Reaction time: 6 h
Yield: 83.7 %

Procedure:
Trifluoroacetic anhydride (3 mL) was added to a dichloromethane solution (6 mL) of ethyl 5-[2-{[(4-methylphenyl)sulfonyl]imino}-5-nitropyridin-1(2H)-yl]-4-oxohexanoate (635 mg) obtained in Production Example 47-4, at room temperature. The reaction liquid was heated up to 40° C., stirred for 6 hours, and then concentrated under reduced pressure. Aqueous saturated sodium hydrogencarbonate solution was added to the residue, and extracted with ethyl acetate. The organic layer was dried with sodium sulfate, concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (ethyl acetate/chloroform/hexane=1/1/1) to obtain the entitled compound (328 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Li]CCCC.[B:19](OC(C)C)([O:24]C(C)C)[O:20]C(C)C.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[N:8]1([C:5]2[CH:6]=[CH:7][C:2]([B:19]([OH:24])[OH:20])=[CH:3][CH:4]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1ccc(N2CCOCC2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OB(O)c1ccc(N2CCOCC2)cc1
Reaction time: 8 h

Procedure:
To a solution of the compound prepared in step 1 (0.3 g) in THF (15 mL) was added n-BuLi (0.74 mL, 2 M in pentane) at 78° C. After 1 h triisopropyl borate (0.86 mL) was added at −78° C. The solution was warmed up slowly from −78° C. to room temperature and was stirred overnight. The solution was added to aqueous NH4Cl, a white precipitate formed, and EtOAc was added. The organic solution was separated, concentrated and co-evaporated with toluene. The residue washed twice with THF and filtered. The filtrate was concentrated and dried under high vacuum to give 0.25 g of light yellow precipitate. LC/MS m/z 208 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C@H:11]1[CH2:16][C@H:15]([NH:17][C:18]([NH:20][C:21]2[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=2)=[O:19])[CH2:14][CH2:13][N:12]1[C:31](OC(C)(C)C)=O)=O.C=O.C([BH3-])#N.[Na+].C1COCC1>C(O)(=O)C.O.CO>[NH:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:9]1[C@H:11]1[CH2:16][C@H:15]([NH:17][C:18]([NH:20][C:21]2[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=2)=[O:19])[CH2:14][CH2:13][N:12]1[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)Nc2ccc(C(F)(F)F)nc2)C[C@@H]1C(=O)Nc1ccccc1N
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CN1CC[C@@H](NC(=O)Nc2ccc(C(F)(F)F)nc2)C[C@@H]1c1nc2ccccc2[nH]1
Temperature: 65 °C
Reaction time: 2 h
Yield: 61.5 %

Procedure:
(2R,4R)-tert-butyl 2-((2-aminophenyl)carbamoyl)-4-(3-(6-(trifluoromethyl)pyridin-3-yl)ureido)piperidine-1-carboxylate (550 mg, 1.05 mmol) was dissolved in acetic acid (5 mL) and stirred at 65° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to remove acetic acid. Then TFA (3 mL) was added to the residue. The resulting solution was stirred at room temperature for 2 hours. The reaction mixture was concentrated to remove TFA and did next reaction without further purification. 37% formaldehyde solution (0.25 mL, 3.2 mmol) in water was added to a solution of the residue in methanol (5 mL) and the reaction mixture was stirred at room temperature for 1 hour, then 1M sodium cyanoborohydride in THF (3.2 mL, 3.2 mmol) was added carefully at 0° C. The reaction mixture was stirred at room temperature for 18 hours and then solvent was evaporated in vacuum. Saturated sodium bicarbonate solution (20 mL) and ethyl acetate (40 mL) were added and the mixture was stirred about 30 min. The organic layer was separated and dried over MgSO4, and concentrated. Product was purified by Companion (ReadySep 40 g, silica gel packed) with CH3OH/CH2Cl2 from 2%-6-8% to give the title compound as an off-white solid 270 mg (52%). LC-MS: 419.2, 417.3 (t=1.7 min).