Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[C:9]3[O:10][CH:11]([CH3:15])[C:12](=[O:14])[NH:13][C:8]=3[CH:7]=[C:6]([CH:16]=O)[CH:5]=2)[CH2:3][CH2:2]1.[CH:18]1([NH:21][C:22](=[O:35])[C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[CH:25][CH:24]=2)[CH2:20][CH2:19]1>>[CH:18]1([NH:21][C:22](=[O:35])[C:23]2[CH:24]=[CH:25][C:26]([N:29]3[CH2:30][CH2:31][N:32]([CH2:16][C:6]4[CH:5]=[C:4]([CH:1]5[CH2:2][CH2:3]5)[C:9]5[O:10][CH:11]([CH3:15])[C:12](=[O:14])[NH:13][C:8]=5[CH:7]=4)[CH2:33][CH2:34]3)=[CH:27][CH:28]=2)[CH2:20][CH2:19]1
Reactant: CC1Oc2c(cc(C=O)cc2C2CC2)NC1=O
Reactant: O=C(NC1CC1)c1ccc(N2CCNCC2)cc1
Product: CC1Oc2c(cc(CN3CCN(c4ccc(C(=O)NC5CC5)cc4)CC3)cc2C2CC2)NC1=O

Procedure:
Using 346A and N-cyclopropyl-4-(piperazin-1-yl)benzamide 284 in the general procedure for reductive aminations, the title compound was obtained as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 0.50-0.57 (m, 2H) 0.61-0.70 (m, 4H) 0.89-0.95 (m, 2H) 1.43 (d, J=6.82 Hz, 3H) 2.03-2.12 (m, 1H) 2.40-2.49 (m, 4H) 2.76-2.83 (m, 1H) 3.19-3.26 (m, 4 H) 3.37 (br. s., 2H) 4.64 (q, J=6.82 Hz, 1H) 6.41 (d, J=1.52 Hz, 1H) 6.67-6.73 (m, 1H) 6.91 (m, J=8.84 Hz, 2H) 7.70 (m, J=8.59 Hz, 2H) 8.17 (d, J=3.54 Hz, 1H) 10.57 (s, 1H). ESI-MS: m/z 461.4 (M+H)+. mp=202.5-207.3° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[N:22][C:23]([CH2:27][CH2:28][CH3:29])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:3]=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(N(CC)C(C)C)(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:13][CH:14]=2)=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[N:22][C:23]([CH2:27][CH2:28][CH3:29])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:3]=1
Reactant: CCCc1ccc2c(Nc3cc(C)ccc3Sc3ccc(O)cc3)ccnc2n1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1ccc2c(Nc3cc(C)ccc3Sc3ccc(OS(C)(=O)=O)cc3)ccnc2n1

Procedure:
The product from Example 6 (100 mg, 0.228 mmol) was reacted with methane sulfonyl chloride (28 mg, 0.251 mmol), N,N-diisopropylethylamine (88.4 mg, 0.684 mmol), and catalytic DMAP in CH2Cl2 for 18 h giving the crude title compound which was purified by HPLC with TFA providing the product as the trifluoroacetic acid (20 mg, 15%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.97 (t, J=7.35 Hz, 3H) 1.77-1.90 (m, 2H) 2.40 (s, 3H) 2.98 (t, J=7.54 Hz, 2H) 3.43 (s, 3H) 6.34 (d, J=6.99 Hz, 1H) 7.19 (d, 2H) 7.27 (d, 2H) 7.36-7.40 (m, 2H) 7.48 (d, 1H) 7.78 (d, J=8.82 Hz, 1H) 8.39 (d, J=6.99 Hz, 1H) 8.91 (d, J=8.46 Hz, 1H); MS (DCI NH3+) 480 m/z (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].O.C(=O)([O-])O.[Na+].[C:19](Cl)(Cl)=[S:20]>C(Cl)(Cl)Cl>[F:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([N:1]=[C:19]=[S:20])[CH:11]=1
Reactant: S=C(Cl)Cl
Reactant: COC(=O)c1ccc(F)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: COC(=O)c1ccc(F)cc1N=C=S
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
Methyl 2-amino-4-fluorobenzoate (7.3 g, 43.2 mmol) was dissolved in chloro-form, followed by addition of water (150 mL) and sodium hydrogencarbonate (36.3 g, 432 mmol). Thiophosgene (3.73 mL, 47.5 mmol) was added and the mixture was stirred at RT for 2 h. Water (250 mL) was added and the mixture was extracted with DCM. The combined organics were dried (MgSO4) and evaporated to give the title compound (8.90 g, 98%).
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[N:6]=[C:7]([NH:10][CH:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][C:18]=4[O:20][CH3:21])[CH2:13][CH2:12]3)[O:8][CH2:9][C:4]=2[CH:3]=1.[NH2:24][C:25]1[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=1>>[CH3:21][O:20][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:19]=1[CH:11]([NH:10][C:7]1[O:8][CH2:9][C:4]3[CH:3]=[C:2]([NH:24][C:25]4[N:30]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:28]=[CH:27][N:26]=4)[CH:23]=[CH:22][C:5]=3[N:6]=1)[CH2:12][CH2:13]2
Reactant: COc1cccc2c1C(NC1=Nc3ccc(Br)cc3CO1)CC2
Reactant: Nc1nccc(C(F)(F)F)n1
Product: COc1cccc2c1C(NC1=Nc3ccc(Nc4nccc(C(F)(F)F)n4)cc3CO1)CC2
Yield: 61.9 %

Procedure:
The title compound (141 mg, 62%), yellow foam, MS (ISP): m/e=456.3 (M+H+), was prepared in accordance with the general method of Example 35 from rac-(6-bromo-4H-benzo[d][1,3]oxazin-2-yl)-(7-methoxy-indan-1-yl)-amine (Example 74) (187 mg, 0.5 mmol) and commercially available 2-amino-4-trifluoromethyl-pyrimidine (163 mg, 1.0 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([CH:13]([N:15]([CH:20]3[CH2:22][CH2:21]3)[C:16]([NH:18][CH3:19])=[S:17])[CH3:14])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.I[CH2:24][CH3:25]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([CH:13]([N:15]([CH:20]3[CH2:21][CH2:22]3)[C:16](=[N:18][CH3:19])[S:17][CH2:24][CH3:25])[CH3:14])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCI
Reactant: CNC(=S)N(C1CC1)C(C)c1nc(-c2cccc(Cl)c2)no1
Solvent: CO
Product: CCSC(=NC)N(C1CC1)C(C)c1nc(-c2cccc(Cl)c2)no1
Yield: 96.1 %

Procedure:
1-{1-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-ethyl}-1-cyclopropyl-3-methyl-thiourea (287 mg, 0.85 mmol) was mixed with iodoethane (484 mg, 3.4 mmol) in MeOH (5 mL) at 60° C. overnight. The reaction mixture was concentrated and basified with saturated sodium carbonate, then extracted with DCM. The organic layer was dried, concentrated to give the title compound (298 mg, 96 %). 1H-NMR: 8.11 (s, 1H), 8.01 (d, 1H), 7.51 (d, 1H), 7.46 (t, 1H), 5.51 (m, 1H), 3.27 (s, 3H), 2.85-3.00 (m, 2H), 2.60 (m, 1H), 1.79 (d, 3H), 1.30 (t, 3H), 0.83 (m)
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:23])=[C:7]([CH:22]=1)[C:8]([NH:10][CH2:11][C:12]12[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH2:13]1)[CH2:19]2)=[O:9].[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C(N(C(C)C)CC)(C)C>CN(C)C=O.O>[Cl:23][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][N:34]2[CH2:33][CH2:32][N:31]([C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])[CH2:36][CH2:35]2)=[CH:22][C:7]=1[C:8]([NH:10][CH2:11][C:12]12[CH2:21][CH:16]3[CH2:15][CH:14]([CH2:20][CH:18]([CH2:17]3)[CH2:19]1)[CH2:13]2)=[O:9]
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CBr)ccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)CC1
Temperature: 60 °C
Yield: 68.1 %

Procedure:
A mixture of 5-bromomethyl-2-chloro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (Example 8b, 0.130 g), 1-tertbutyloxycarbonylpiperazine (0.074 g) and diisopropylethylamine (6.3 ml) in dimethylformamide (3 ml) was heated at 60° C. for 3 h. The mixture was diluted with water (10 ml) and extracted with ethyl acetate (3×10 ml). The organic layer was dried over magnesium sulfate, filtered and the filtrate concentrated under reduced pressure. The crude material was purified on a silica gel eluting with dichloromethane/ethanol (0-20% gradient) to afford the title compound as a white foam (0.112 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]=2[CH2:16][OH:17])=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl.CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:13][CH2:12][C:11]([CH3:14])([CH3:15])[CH2:10][C:9]=2[CH:16]=[O:17])=[CH:6][CH:7]=1
Reactant: CC1(C)CCC(c2ccc(Cl)cc2)=C(CO)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOCC
Product: CC1(C)CCC(c2ccc(Cl)cc2)=C(C=O)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of EXAMPLE 75C (2.8 g) in dichloromethane (50 mL) was added Dess-Martin Periodinane (5.68 g). The reaction mixture was stirred at room temperature for 3 hours and diluted with ether and washed with 5% NaOH and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography using 20% ethyl acetate in hexanes to provide the title compound.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:45])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:41][CH3:42])([C:22]3[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([OH:39])([C:35]([F:38])([F:37])[F:36])[C:31]([F:34])([F:33])[F:32])=[C:24]([CH3:40])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:43])=[CH:9][C:8]=1[Cl:44]>CO.O1CCCC1>[Cl:44][C:8]1[CH:9]=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:41][CH3:42])([C:22]3[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([OH:39])([C:31]([F:32])([F:33])[F:34])[C:35]([F:37])([F:38])[F:36])=[C:24]([CH3:40])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:43])[CH:11]=[CH:12][C:7]=1[CH2:6][C:5]([OH:45])=[O:4]
Reactant: CCC(CC)(c1ccc(/C=C/C(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)c(Cl)c2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(CC)(c1ccc(/C=C/C(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(-c2ccc(CC(=O)O)c(Cl)c2)c(C)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 54.4 %

Procedure:
A 1 N sodium hydroxide aqueous solution (0.019 mL, 0.019 mmol) was added to a solution of (3-chloro-4′-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-1-butenyl)-phenyl]-propyl}-2′-methyl-biphenyl-4-yl)acetic acid methyl ester (Example 73-(1); 3.9 mg, 0.006 mmol) in methanol-tetrahydrofuran (1:1, 1 mL), and the mixture was stirred at 60° C. for one hour. Then, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform:methanol=8:3, saturated with water) to give the target compound as a colorless oil (2.0 mg, 53%).
Reaction SMILES: [C:1]1(=[O:15])[C:9]2[CH:8]=[C:7]3[CH:10]=[CH:11][CH:12]=[CH:13][C:6]3=[CH:5][C:4]=2[C:3](=[O:14])[NH:2]1.[CH2:16]([O:18][C:19](=[O:22])[CH2:20]Br)[CH3:17]>>[CH2:16]([O:18][C:19](=[O:22])[CH2:20][N:2]1[C:3](=[O:14])[C:4]2[CH:5]=[C:6]3[CH:13]=[CH:12][CH:11]=[CH:10][C:7]3=[CH:8][C:9]=2[C:1]1=[O:15])[CH3:17]
Reactant: O=C1NC(=O)c2cc3ccccc3cc21
Reactant: CCOC(=O)CBr
Product: CCOC(=O)CN1C(=O)c2cc3ccccc3cc2C1=O

Procedure:
2 g (10.1 mmol) Benzo[f]isoindole-1,3-dione was reacted with bromoacetic acid ethyl ester analogously to Example D-21a. The crude product obtained was partitioned between ethyl acetate and water. Organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated to give 2.68 g (9.5 mmol) of product. 1H NMR (200 MHz, CDCl3) δ 8.36 (s, 2 H), 8.05 (m, 2 H), 7.68 (m, 2 H), 4.49 (s, 2 H), 4.22 (q, J=7.0 Hz, 2 H), 1.29 (t, 7.0 Hz, 3 H).
Reaction SMILES: [CH2:1]([N:3]([CH2:36][CH3:37])[CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[CH:31]=[CH:30][C:21]2[C:22]3[CH:23]=[CH:24][O:25][C:26]=3[CH2:27][CH2:28][O:29][C:20]=2[C:19]=1[C:32]([O:34][CH3:35])=[O:33])(=[O:16])=[O:15])[CH3:2]>C(O)C.C(O)=O>[CH2:36]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[CH:31]=[CH:30][C:21]2[C:22]3[CH:23]=[CH:24][O:25][C:26]=3[CH2:27][CH2:28][O:29][C:20]=2[C:19]=1[C:32]([O:34][CH3:35])=[O:33])(=[O:16])=[O:15])[CH3:37]
Reactant: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCCc1occc1-2
Solvent: CCO
Solvent: O=CO
Product: CCN(CC)CCCc1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCCc1occc1-2
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
Methyl 8-[2((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-4,5-dihydro-3,6-dioxabenzo[e]azulene-7-carboxylate (Intermediate 5, 0.147 g) was suspended in ethanol. Formic acid (2 drops) was added and the flask was evacuated and purged with nitrogen gas. Palladium hydroxide (20% wt, 0.015 g) was added and nitrogen was replaced by hydrogen and the mixture was stirred at room temperature under an atmosphere of hydrogen for 1 hour. The mixture was filtered through a pad of Celite and washed with ethanol. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM, with a gradient of 2.5-10% to give methyl 8-[2-(3-diethylaminopropyl)-4-fluorobenzenesulfonylamino]-4,5-dihydro-3,6-dioxabenzo[e]azulene-7-carboxylate (0.134 g) as a yellow glassy solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)=[O:4].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.FC(N(C)C)=[N+](C)C.[C:39]([NH2:48])([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([CH3:41])[CH3:40]>O.CN(C=O)C>[N+:14]([C:8]1[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:13][C:9]=1[C:10](=[O:12])[NH:48][C:39]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([CH3:41])[CH3:40])([O-:16])=[O:15]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(C(=O)O)c1
Reactant: CC(C)(N)c1ccccc1
Agent: CN(C)C(F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc([N+](=O)[O-])c(C(=O)NC(C)(C)c2ccccc2)c1
Reaction time: 0.5 h
Yield: 71.6 %

Procedure:
A mixture of 5-(methoxycarbonyl)-2-nitrobenzoic acid (0.12 g, 0.53 mmol), DMF (2.50 mL), triethylamine (0.22 mL, 1.6 mmol) and fluoro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (0.17 g, 0.64 mmol) was stirred for 30 min and cumylamine (0.092 mL, 0.64 mmol) was added. The reaction mixture was stirred at rt for 1 d. Water was added and the mixture was extracted with EtOAc (2×). The combined organic phases were then washed with water, and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (50% to 100% EtOAc/hexanes) to afford methyl 4-nitro-3-[(2-phenylpropan-2-yl)carbamoyl]benzoate (0.13 g, 70%). LC-MS: (FA) ES+ 343.
Reaction SMILES: [C:1]([C:5]1[CH:25]=[CH:24][C:8]([O:9][CH:10]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CS(O[CH2:31][CH2:32][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>>[C:36]([O:35][C:34]([NH:33][CH2:32][CH2:31][O:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][CH:10]([O:9][C:8]2[CH:24]=[CH:25][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:6][CH:7]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:22][CH:21]=1)=[O:40])([CH3:39])([CH3:38])[CH3:37]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)Oc1ccc(C(C)(C)C)cc1
Reactant: CC(C)(C)OC(=O)NCCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C(Cc1ccc(OCCNC(=O)OC(C)(C)C)cc1)Oc1ccc(C(C)(C)C)cc1
Yield: 93.1 %

Procedure:
In a similar manner to that described in Reference example 25, a reaction was carried out using ethyl 2-(4-t-butylphenoxy)-3-(4-hydroxyphenyl)propionate (2.37 g), which is the product of Reference example 36(b), t-butyl 2-methanesulfonyloxyethylcarbamate (3.60 g) and potassium carbonate (4.78 g) and the reaction mixture was treated to afford the title compound (3.13 g) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14](Cl)=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:17][C@H:18]1[CH2:23][N:22]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31][CH3:32])=[CH:27][CH:26]=2)[CH2:21][CH2:20][N:19]1[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([N:31]([CH3:32])[C:28]3[CH:27]=[CH:26][C:25]([CH2:24][N:22]4[CH2:21][CH2:20][N:19]([C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])[C@@H:18]([CH3:17])[CH2:23]4)=[CH:30][CH:29]=3)=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Reactant: O=C(Cl)C1CCN(c2ccc(F)cc2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1CN(Cc2ccc(N(C)C(=O)C3CCN(c4ccc(F)cc4)CC3)cc2)CCN1C(=O)OC(C)(C)C
Reaction time: 3 h

Procedure:
The acid chloride from step 1 was taken up in DCM (2.5 mL) and added drop-wise to 1,1-dimethylethyl (2S)-2-methyl-4-{[4-(methylamino)phenyl]methyl}-1-piperazinecarboxylate (D3) (0.121 g, 0.38 mmol) in DCM (2.5 mL), followed by triethylamine (0.080 mL, 0.57 mmol). The reaction mixture was stirred for 3 h under argon, then the solvent was removed by evaporation. The residue was partitioned between DCM (30 mL) and water (30 mL). The aqueous was re-extracted with DCM (30 mL) and the combined organic layers were dried and concentrated to yield the title compound as a yellow oil. δH (CDCl3, 400 MHz) 7.40 (2H, d), 7.15 (2H, d), 6.89 (2H, m), 6.80 (2H, m), 4.20 (1H, br.s), 3.82 (1H, d), 3.50 (4H, m), 3.27 (3H, s), 3.10 (1H, m), 2.76 (1H, d), 2.58 (1H, d), 2.35 (3H, m), 2.17 (1H, m), 2.00 (3H, m), 1.70 (2H, d), 1.46 (9H, s), 1.22 (3H, d). MS (ES): MH+ 525.4.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].[NH2:14][C:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=1.C(N(CC)CC)C.CN(C)P(N(C)C)(N(C)C)=O>O>[OH:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][CH:25]=1
Reactant: OCCCCCCCCCCCBr
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccc(NCCCCCCCCCCCO)cc1

Procedure:
A solution of 16 g. of 11-bromoundecanol, 9.9 g. of ethyl 4-aminobenzoate, and 6.0 g. of triethylamine in 50 ml. of hexamethylphosphoramide is stirred at 70° C. under argon for 128 hours. The resulting solution is cooled, diluted with water, and filtered. Recrystallization of the solid from acetonitrile affords ethyl 4-(11-hydroxyundecylamino)benzoate as a white, crystalline solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][NH:7][C@H:6]([C:9]2[NH:10][C:11]([C:14]3[CH:19]=[C:18]4[CH2:20][O:21][C:22]5[CH:53]=[C:52]6[C:25]([CH:26]=[CH:27][C:28]7[N:32]=[C:31]([C@@H:33]8[CH2:37][CH2:36][CH2:35][N:34]8[C:38](=[O:51])[C@H:39]([NH:46][C:47](=[O:50])[O:48][CH3:49])[C:40]8[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=8)[NH:30][C:29]=76)=[CH:24][C:23]=5[C:17]4=[CH:16][CH:15]=3)=[CH:12][N:13]=2)[CH2:5]1.[CH3:54][O:55][C@H:56]([CH3:66])[C@H:57]([NH:61][C:62]([O:64][CH3:65])=[O:63])[C:58](O)=[O:59].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>[CH3:65][O:64][C:62]([NH:61][C@H:57]([C:58]([N:7]1[CH2:8][C@@H:4]([CH2:3][O:2][CH3:1])[CH2:5][C@H:6]1[C:9]1[NH:10][C:11]([C:14]2[CH:19]=[C:18]3[CH2:20][O:21][C:22]4[CH:53]=[C:52]5[C:25]([CH:26]=[CH:27][C:28]6[N:32]=[C:31]([C@@H:33]7[CH2:37][CH2:36][CH2:35][N:34]7[C:38](=[O:51])[C@H:39]([NH:46][C:47](=[O:50])[O:48][CH3:49])[C:40]7[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=7)[NH:30][C:29]=65)=[CH:24][C:23]=4[C:17]3=[CH:16][CH:15]=2)=[CH:12][N:13]=1)=[O:59])[C@@H:56]([CH3:66])[O:55][CH3:54])=[O:63]
Reactant: COC(=O)N[C@H](C(=O)O)[C@@H](C)OC
Reactant: COC[C@@H]1CN[C@H](c2ncc(-c3ccc4c(c3)COc3cc5c(ccc6nc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]c65)cc3-4)[nH]2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC[C@H]1C[C@@H](c2ncc(-c3ccc4c(c3)COc3cc5c(ccc6nc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]c65)cc3-4)[nH]2)N(C(=O)[C@@H](NC(=O)OC)[C@@H](C)OC)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of methyl {(1R)-2-[(2S)-2-(9-{2-[(2S,4S)-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate (51 mg, 0.072 mmol), (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid (14 mg, 0.072 mmol), HATU (30 mg, 0.079 mmol) and 0.4 mL 10% DIPEA in DMF was stirred at room temperature for 1 hour. The product was purified by reverse phase HPLC. The product was converted to the free base by dissolution in 2 mL 1:1 acetonitrile:methanol and passage through a prepacked cartridge of polymer supported carbonate. The eluent was concentrated, the taken up in 1% TFA in 1:1 acetonitrile:water, frozen, and lyophilized to give the product as a trifluoroacetate salt. (24 mg)
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([Li])=[CH:2]1.[Cl:7][C:8]1[CH:21]=[CH:20][C:11]([CH:12]=[N:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1>>[Cl:7][C:8]1[CH:21]=[CH:20][C:11]([CH:12]([NH:13][C:14]2[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=2)[C:3]2[CH:4]=[CH:5][O:1][CH:2]=2)=[CH:10][CH:9]=1
Reactant: [Li]c1ccoc1
Reactant: Clc1ccc(C=Nc2ccncc2)cc1
Product: Clc1ccc(C(Nc2ccncc2)c2ccoc2)cc1

Procedure:
The title compound is prepared in a similar manner to Examples 5,6 and 7 from 3-furyl lithium (obtained by treating 3-iodofuran with butyl lithium) and 4-(p-chlorobenzylideneamino)pyridine.
Reaction SMILES: C(P(=O)(OCC)OCC)#N.[F:11][C:12]1[CH:13]=[C:14]([C@H:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([CH:24]=[CH2:25])[NH:19]2)[CH:15]=[CH:16][CH:17]=1.[CH:26]([CH2:28][C:29](O)=[O:30])=[CH2:27].Cl>CN(C=O)C.C(OCC)(=O)C.C(N(CC)CC)C>[F:11][C:12]1[CH:13]=[C:14]([C@H:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([CH:24]=[CH2:25])[N:19]2[C:29](=[O:30])[CH2:28][CH:26]=[CH2:27])[CH:15]=[CH:16][CH:17]=1
Reactant: C=CCC(=O)O
Reactant: C=C[C@@H]1CCC[C@H](c2cccc(F)c2)N1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCC(=O)N1[C@H](C=C)CCC[C@@H]1c1cccc(F)c1
Temperature: 25 °C
Reaction time: 27 h

Procedure:
Diethyl cyanophosphonate (1.78 mL) was added to a solution of (2R*,6S*)-2-(3-fluorophenyl)-6-vinylpiperidine (748 mg), vinylacetic acid (0.96 mL), and triethylamine (3.1 mL) in DMF (15 mL) at room temperature, and the reaction solution was stirred at room temperature for 27 hours. Ethyl acetate and 1 N hydrochloric acid were added to the reaction solution, and the organic layer was separated. The resulting organic layer was sequentially washed with saturated sodium bicarbonate water and brine, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 587 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH:12][NH2:13])=[O:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24](O)=O)=[CH:18][CH:17]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:11][C:24]([CH2:23][CH2:22][C:19]4[CH:18]=[CH:17][C:16]([O:15][CH3:14])=[CH:21][CH:20]=4)=[N:13][N:12]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: NNC(=O)c1ccc2occc2c1
Reactant: COc1ccc(CCC(=O)O)cc1
Product: COc1ccc(CCc2nnc(-c3ccc4occc4c3)o2)cc1
Yield: 53 %

Procedure:
In the same manner as in Example 14 and using 1-benzofuran-5-carbohydrazide instead of 1H-benzotriazole-5-carbohydrazide and 3-(4-methoxyphenyl)propionic acid instead of 3-(3-cyanophenyl)propionic acid, the title compound (yield 53%) was obtained as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[C:7](F)=[C:6]([N+:9]([O-])=O)[CH:5]=[CH:4][C:3]=1[F:12].CC[N:15]([CH:19]([CH3:21])[CH3:20])C(C)C.C1(N)CC1.[NH4+].[Cl-]>CC#N.[Fe]>[Br:1][C:2]1[C:3]([F:12])=[CH:4][CH:5]=[C:6]([NH2:9])[C:7]=1[NH:15][CH:19]1[CH2:21][CH2:20]1
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1F
Reactant: CCN(C(C)C)C(C)C
Agent: [Fe]
Agent: NC1CC1
Agent: [Cl-]
Solvent: CC#N
Product: Nc1ccc(F)c(Br)c1NC1CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.9 %

Procedure:
To a solution of 2-bromo-1,3-difluoro-4-nitrobenzene (1.19 g, 5.0 mmol) in MeCN (10 mL) were added DIPEA (1.74 mL, 10.0 mmol) and cyclopropylamine (360 mL, 5.17 mmol). The reaction mixture was stirred at RT for 4 h. The volatiles were removed under reduced pressure and the resulting residue was partitioned between DCM and water. The organic fraction was dried, concentrated in vacuo and the resulting residue taken up in a 3:1 mixture of MeOH:water (40 mL). NH4Cl (1.53 g, 28.6 mmol) and iron powder (1.06 g, 4.76 mmol) were added and the reaction mixture heated at 80° C. for 3 h. After cooling to RT, the mixture was filtered through a pad of Celite® and washed with additional MeOH. The filtrate was concentrated in vacuo and the resulting residue partitioned between DCM and an aqueous solution of NaHCO3. The organic fraction was dried and concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-5% MeOH in EtOAc) to afford the title compound as a brown oil (759 mg, 62% over 2 steps). LCMS (Method C): RT 2.97 min [M+H]+ 245.02