Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH2:22][CH:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[N:16]=3)[C:12]([Cl:29])=[CH:11][N:10]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.FC(F)(F)S(O[CH2:43][CH2:44][O:45][C:46]([F:49])([F:48])[F:47])(=O)=O>C(Cl)(Cl)Cl>[Cl:29][C:12]1[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH2:22][CH:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:16]=2)=[CH:14][C:9]([NH:8][C@H:5]2[CH2:6][CH2:7][C@H:2]([NH:1][CH2:43][CH2:44][O:45][C:46]([F:49])([F:48])[F:47])[CH2:3][CH2:4]2)=[N:10][CH:11]=1
Reactant: O=S(=O)(OCCOC(F)(F)F)C(F)(F)F
Reactant: N[C@H]1CC[C@H](Nc2cc(-c3cccc(NCC4CCOCC4)n3)c(Cl)cn2)CC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: FC(F)(F)OCCN[C@H]1CC[C@H](Nc2cc(-c3cccc(NCC4CCOCC4)n3)c(Cl)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of N2′-(trans-4-aminocyclohexyl)-5′-chloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine (42 mg, 0.10 mmol) and triethylamine (0.028 mL, 0.20 mmol) in chloroform (0.4 ml) was added 2-(trifluoromethoxy)ethyl trifluoromethanesulfonate (39 mg, 0.15 mmol). The mixture was stirred at ambient temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, purified by reverse phase HPLC, and lyophilized to give 32 mg of 5′-chloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-N2′-(trans-4-(2-(trifluoromethoxy)ethylamino)cyclohexyl)-2,4′-bipyridine-2′,6-diamine as its TFA salt. LCMS (m/z): 528.4 (MH+), retention time=0.53 min.; 1H NMR (400 MHz, DMSO-d6) d ppm 1.09-1.34 (m, 4H) 1.35-1.54 (m, 2H) 1.55-1.69 (m, 2H) 1.73-1.89 (m, 1H) 1.94-2.17 (m, 4H) 3.04-3.15 (m, 1H) 3.14-3.20 (m, 2H) 3.20-3.30 (m, 2H) 3.30-3.47 (m, 2H) 3.55-3.72 (m, 1H) 3.84 (dd, J=11.15, 2.54 Hz, 2H) 4.35 (t, J=4.70 Hz, 2H) 6.65 (s, 1H) 6.67-6.83 (m, 2H) 7.05 (br. s., 0H) 7.46-7.68 (m, 0H) 8.06 (s, 0H) 8.82 (d, J=3.52 Hz, 2H)
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([OH:15])=O)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[NH2:47][C:48]1[CH:49]=[C:50]2[C:54](=[CH:55][CH:56]=1)[NH:53][C:52]([CH:57]([CH3:60])[CH2:58][OH:59])=[CH:51]2>C(#N)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:47][C:48]4[CH:49]=[C:50]5[C:54](=[CH:55][CH:56]=4)[NH:53][C:52]([CH:57]([CH3:60])[CH2:58][OH:59])=[CH:51]5)=[O:15])[CH2:11][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(CO)c1cc2cc(N)ccc2[nH]1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(CO)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 51.2 %

Procedure:
To a solution of 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (0.10 g, 0.49 mmol) in acetonitrile (2.0 mL) were added HBTU (0.185 g, 0.49 mmol) and Et3N (205 μL, 1.47 mmol) at room temperature. The mixture was allowed to stir at room temperature for 10 minutes before a slurry of 2-(5-amino-1H-indol-2-yl)propan-1-ol (0.093 g, 0.49 mmol) in acetonitrile (2.7 mL) was added. After addition, the reaction mixture was stirred at room temperature for 5.5 h. The solvent was evaporated under reduced pressure and the residue was dissolved in dichloromethane. The organic layer washed with 1 N HCl (1×3 mL) and saturated aqueous NaHCO3 (1×3 mL). The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The crude material was purified by column chromatography on silica gel (ethyl acetate/hexane=13/7) to give 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-(1-hydroxypropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (0.095 g, 51%). 1H NMR (400 MHz, DMSO-d6) δ 10.74 (s, 1H), 8.38 (s, 1H), 7.55 (s, 1H), 7.14 (d, J=8.6 Hz, 1H), 7.02-6.90 (m, 4H), 6.06 (s, 1H), 6.02 (s, 2H), 4.76 (t, J=5.3 Hz, 1H), 3.68-3.63 (m, 1H), 3.50-3.44 (m, 1H), 2.99-2.90 (m, 1H), 1.41-1.38 (m, 2H), 1.26 (d, J=7.0 Hz, 3H), 1.05-1.02 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:21])[CH3:20])[CH:15]=[CH:16][CH:17]=2)[C:9]2[C:4](=[CH:5][C:6]([O:24][CH3:25])=[C:7]([O:22][CH3:23])[CH:8]=2)[N:3]=1.O1CCCC1.[CH3:31][NH2:32].[Cl-].[Na+]>C(OCC)(=O)C.CO>[CH3:23][O:22][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[O:24][CH3:25])[N:3]=[C:2]([NH:32][CH3:31])[N:11]=[C:10]2[C:12]1[CH:13]=[C:14]([NH:18][C:19](=[O:21])[CH3:20])[CH:15]=[CH:16][CH:17]=1
Reactant: COc1cc2nc(Cl)nc(-c3cccc(NC(C)=O)c3)c2cc1OC
Reactant: CN
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: CNc1nc(-c2cccc(NC(C)=O)c2)c2cc(OC)c(OC)cc2n1
Temperature: 50 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
To 353 mg (0.96 mmol) of N-[3-(2-chloro-6,7-dimethoxyquinazolin-4-yl)phenyl]acetamide, tetrahydrofuran (2.06 mL), and methanol (1.03 mL) was added a methanol solution (2.06 mL) of 40% methylamine, and the mixture was reacted at 90° C. for 9 hours. The mixture was allowed to cool and then poured into a mixed solution of ethyl acetate (30 mL) and 5% w/w sodium chloride solution (30 mL) while washing with tetrahydrofuran (30 mL) to extract the organic layer. The organic layer was washed with 5% w/w sodium chloride solution (30 mL) and then concentrated under reduced pressure. To the concentration residue was added t-butyl methyl ether (3 mL), and the mixture was crystallized with a spatula and then suspended by stirring at 50° C. for 2 hours. The mixture was allowed to cool gradually, and then the precipitated crystals were collected by filtration and dried to give 318 mg of a target product (yield: 91.1%).
Reaction SMILES: [C:1]1([CH2:7][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[CH:18]=[N:19][NH:20][CH:21]=3)[CH:12]=2)[C:9]#[N:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N.O.[H][H]>C(O)C.[Ni]>[C:1]1([CH2:7][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[CH:18]=[N:19][NH:20][CH:21]=3)[CH:12]=2)[CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CC(Cc1ccccc1)c1cccc(-c2cn[nH]c2)c1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: O
Solvent: CCO
Product: NCC(Cc1ccccc1)c1cccc(-c2cn[nH]c2)c1

Procedure:
To a solution of the product of Example 2 (70 mg, 0.256 mmol, 1.0 equiv) in ethanol (25 ml) was added concentrated ammonia (0.5 ml) and Raney Nickel (approximately 0.5 ml of the water suspension) and the reaction mixture was subjected to a hydrogen atmosphere for 17 hours. The mixture was filtered through Celite® and the mother liquor was concentrated under reduced pressure to give the title compound which was purified by preparative liquid chromatography. (LC/MS: (PS-A) Rt 1.89 [M+H]+ 278.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[CH:12]=[O:13].[BH4-].[Na+].O.C(OCC)(=O)C>CO>[Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:10])([F:9])[F:11])[C:3]=1[CH2:12][OH:13]
Reactant: Cn1nc(C(F)(F)F)c(C=O)c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: Cn1nc(C(F)(F)F)c(CO)c1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 82.3 %

Procedure:
A solution of 10.0 g (47.0 mmoles) of 5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde dissolved in 100 ml of methanol was cooled to 0° C. Thereto was gradually added 2.1 g (56.5 mmoles) of sodium borohydride. The mixture was stirred at room temperature for 2 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water and extraction with ethyl acetate was conducted. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to reduced pressure distillation to remove the solvent contained therein, to obtain 8.3 g (yield: 82.2%) of (5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=O.O.[NH2:21][NH2:22]>C(O)COCCO>[NH2:1][C:2]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:3]=1[C:4](=[N:21][NH2:22])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12]
Reactant: NN
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1Cl
Solvent: O
Solvent: OCCOCCO
Product: NN=C(c1cc([N+](=O)[O-])ccc1N)c1ccccc1Cl

Procedure:
In the manner given in Preparation 1, 2-amino-2'-chloro-5-nitrobenzophenone is refluxed with hydrazine hydrate in diethylene glycol to give 2-amino-2'-chloro-5-nitrobenzophenone hydrazone.
Reaction SMILES: [CH3:1][C:2]1([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C@@H:18]4[CH2:19][CH2:20][CH2:21][CH2:22][C@H:17]4[NH:16][C:15]3=[O:23])[CH2:10][CH2:9]2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.Cl[C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35].C([O-])(O)=O.[Na+]>ClCCl>[O:23]=[C:15]1[N:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:2]3([CH3:1])[CH2:7][CH2:6][N:5]([C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35])[CH2:4][CH2:3]3)[CH2:9][CH2:10]2)[C@@H:18]2[CH2:19][CH2:20][CH2:21][CH2:22][C@H:17]2[NH:16]1
Reactant: CC(C)OC(=O)Cl
Reactant: CC1(N2CCC(N3C(=O)N[C@@H]4CCCC[C@H]43)CC2)CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)OC(=O)N1CCC(C)(N2CCC(N3C(=O)N[C@@H]4CCCC[C@H]43)CC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51 %

Procedure:
A solution of (3aR,7aR)-1-[1-(4-methyl-4-piperidyl)-4-piperidyl]-3a,4,5,6,7,7a-hexahydro-3H-benzoimidazol-2-one (HCl salt, 99 mg, 0.25 mmol) and diisopropylethylamine (129.3 mg, 1.0 mmol) in dry dichloromethane (5 mL) at 0° C. was added dropwise with a solution of 1.0 N isopropyl chloroformate in dichloromethane (0.3 mL, 0.3 mmol) and was stirred at room temperature for 3 h. Saturated NaHCO3 (5 mL) was added followed by dichloromethane (20 mL). The phases were separated and the aqueous phase was extracted with dichloromethane (2×10 mL). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified with preparative LC/MS (high pH) to give the title compound (52 mg, 51%). 1H NMR (400 MHz, METHANOL-D4) δ ppm 0.98 (s, 3H), 1.21 (d, J=6.25 Hz, 6H), 1.30-1.51 (m, 6H), 1.61 (d, J=11.33 Hz, 1H), 1.67-1.89 (m, 7H), 1.95 (d, J=7.42 Hz, 1H), 2.13-2.34 (m, 3H), 2.85-3.16 (m, 4H), 3.28-3.41 (m, 2H), 3.47-3.68 (m, 3H), 4.77-4.85 (m, 1H). MS (M+1): 407.3.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([CH:51]4[CH2:56][CH2:55][CH2:54][CH:53]([C:57]([O:59][CH3:60])=[O:58])[CH2:52]4)[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1.[F:61][C:62]([F:73])([F:72])[C:63]1[CH:71]=[CH:70][C:66]([C:67](Cl)=[O:68])=[CH:65][CH:64]=1>>[O:50]=[C:47]1[C:48]2[C:44](=[CH:43][CH:42]=[C:41]([C:38]3[CH:37]=[CH:36][C:35]([NH:34][C:67](=[O:68])[C:66]4[CH:70]=[CH:71][C:63]([C:62]([F:61])([F:72])[F:73])=[CH:64][CH:65]=4)=[CH:40][CH:39]=3)[CH:49]=2)[CH2:45][N:46]1[CH:51]1[CH2:56][CH2:55][CH2:54][CH:53]([C:57]([O:59][CH3:60])=[O:58])[CH2:52]1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)C1CCCC(N2Cc3ccc(-c4ccc(N)cc4)cc3C2=O)C1
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: COC(=O)C1CCCC(N2Cc3ccc(-c4ccc(NC(=O)c5ccc(C(F)(F)F)cc5)cc4)cc3C2=O)C1
Yield: 82 %

Procedure:
The compound of example 550 was prepared analogous to compound of example 97 by reaction of compound of example 543 with 4-trifluoromethyl benzoyl chloride.
Reaction SMILES: [C:1]([O:5][C:6]1[C:11]([C:12](OCC)=[O:13])=[CH:10][N:9]=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+].O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([O:5][C:6]1[C:11]([CH:12]=[O:13])=[CH:10][N:9]=[CH:8][N:7]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cncnc1OC(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)Oc1ncncc1C=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 108.4 %

Procedure:
After dissolving 976 mg of ethyl 4-tert-butoxypyrimidine-5-carboxylate in 15 ml of toluene, the solution was cooled to −78° C. 3.2 ml of diisobutylaluminium hydride (1.5 M, toluene solution) was added dropwise while stirring, and then after 30 minutes, an aqueous solution of potassium sodium (+)-tartrate was added and the mixture was stirred at room temperature. Water was added to the reaction solution and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine in that order and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain 0.85 g of crude 4-tert-butoxypyrimidine-5-carboxaldehyde.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:16][CH2:15][C:14]([C:17]([O:19]C(C)(C)C)=[O:18])=[CH:13][C:12]=3[CH:24]=2)=[CH:4][CH:3]=1.Cl.C(OCC)(=O)C>CCCCCC>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:16][CH2:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][C:12]=3[CH:24]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)OC(C)(C)C)CO3)cc1
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CO3)cc1
Reaction time: 16 h
Yield: 86.4 %

Procedure:
To tert-butyl 6-(4-methylphenyl)-2H-1-benzopyran-3-carboxylate (3.00 g) was added 4N hydrochloric acid-ethyl acetate (10 ml) at room temperature, and the mixture was stirred for 16 hours. To the reaction mixture was added hexane, and crystal was collected by filtration and washed with hexane to give 6-(4-methylphenyl)-2H-1-benzopyran-3-carboxylic acid (2.14 g) as pale yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[NH2:6].C(N(CC)CC)C.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[CH2:19]([NH:6][C:5]1[CH:7]=[C:8]([O:10][CH3:11])[CH:9]=[C:3]([O:2][CH3:1])[CH:4]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COc1cc(N)cc(OC)c1
Reactant: BrCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(NCc2ccccc2)cc(OC)c1
Reaction time: 0.04 h

Procedure:
N-benzyl-3,5-dimethoxyaniline was prepared using a system (FRX200, Syrris Limited) including a microflow reactor. For this purpose, 76 mg (0.5 mmol) of 3,5-dimethoxyaniline and 5 ml of dimethylformamide were added to the first storage unit of the system including the microflow reactor, and then 70 μl (0.5 mmol) of triethylamine was added thereto. Meanwhile, 60 μl (0.5 mmol) of benzyl bromide and 5 ml of dimethylformamide were added to the second storage unit of the system. The reactants included in the first and second storage units were transferred through the first and second flow channels to the mixing unit, and then transferred through the third flow channel into the microflow reactor including microchannels. The first and second flow channels could transfer 360 μl (180 μl for each flow channel) of the reactants to the microflow reactor. The microflow reactor was set at a capacity of 250 μl, a temperature of 225° C. and a pressure of 8 bar. The reactants in the first and second storage units were set such that they were passed through the first to third flow channels at a flow rate of 0.05 ml/min and introduced into the microflow reactor. Also, the residence time of the reactants in the microflow reactor was set at 2.5 minutes.
Reaction SMILES: C([N:8]1[C@@H:12]([CH2:13][CH2:14][CH3:15])[CH2:11][CH2:10][C@@H:9]1[CH2:16][CH2:17][CH3:18])C1C=CC=CC=1.C([O-])=O.[NH4+].O.[OH-].[Na+]>CO.[OH-].[OH-].[Pd+2]>[CH2:16]([C@H:9]1[CH2:10][CH2:11][C@H:12]([CH2:13][CH2:14][CH3:15])[NH:8]1)[CH2:17][CH3:18]
Reactant: CCC[C@H]1CC[C@H](CCC)N1Cc1ccccc1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: CCC[C@H]1CC[C@H](CCC)N1

Procedure:
Dissolve 1.56 g trans-1-benzyl-2,5-dipropylpyrrolidine from the Step C above in 100 mL methanol and add 4.01 g ammonium formate and 156 mg Pd(OH)2/C. Let the reaction mixture stir under nitrogen over night. Filter the reaction mixture through Celite to remove the catalyst. Concentrate the filtrate under reduced pressure to give a white solid residue. Suspend it in a small amount of water, add 5 mL 5 N NaOH solution, extract with ether several times, wash the combined ether solution with saturated brine, dry over anhydrous Na2SO4, and evaporate to give the title compound as yellow liquid. 1H NMR (CDCl3, 500 MHz) 3.11˜3.16 (m, 2H), 1.91˜1.98 (m, 2H), 1.26˜1.50 (m, 10H), 0.93 (t, J=7.1 Hz, 6H). LC-MS: 1.89 min. (M+H=156.1).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([O:27]C(C)(C)C)=[O:26])=[CH:21][CH:20]=2)=[C:4]([Cl:17])[CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][CH:7]2[C:12]([O:14][CH2:15][CH3:16])=[O:13].FC(F)(F)C(O)=O>ClCCl>[Br:1][C:2]1[C:3]([O:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]([OH:27])=[O:26])=[CH:23][CH:24]=2)=[C:4]([Cl:17])[CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][CH:7]2[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C1CCOc2c1cc(Cl)c(Oc1ccc(C(=O)OC(C)(C)C)cc1)c2Br
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1CCOc2c1cc(Cl)c(Oc1ccc(C(=O)O)cc1)c2Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a stirred solution of ethyl 8-bromo-7-(4-(tert-butoxycarbonyl)phenoxy)-6-chlorochroman-4-carboxylate (0.26 g, 0.51 mmol) in dichloromethane (5 mL) at ambient temperature was added trifluoroacetic acid (5 mL). The resulting solution was stirred at ambient temperature for 30 minutes. The solution was concentrated and the residual glassy solid was redissolved in ethyl acetate (2 mL). Hexanes (10 mL) were added, and after mixing for a few minutes, the product solidified. The mixture was concentrated to afford 4-(8-bromo-6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid as a light brown powder (0.23 g, 99% yield).
Reaction SMILES: [C:1]1([CH:7]([N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)[C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[N:14][N:13](O)[C:12]=3[CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].BrCC(OCC)=O.Cl>CS(C)=O>[C:1]1([CH:7]([N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)[C:8]2[CH:9]=[CH:10][C:11]3[NH:15][N:14]=[N:13][C:12]=3[CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: On1nnc2ccc(C(c3ccccc3)n3cncn3)cc21
Agent: CCOC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: c1ccc(C(c2ccc3[nH]nnc3c2)n2cncn2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 79.6 %

Procedure:
A mixture of 5.85 parts of 6-[phenyl(1H-1,2,4-triazol-1-yl)methyl]-1H-benzotriazol-1-ol, 1.4 parts of potassium carbonate and 27.5 parts of dimethyl sulfoxide was stirred for 30 minutes at 50° C. After cooling, 3.55 parts of ethyl 2-bromoacetate were added and the whole was stirred for 2 hours at room temperature. Another portion of 1.4 parts of potassium carbonate was added. After stirring for 3 hours at 50° C., the mixture was cooled and 2.0 parts of concentrated hydrochloric acid were added. The dimethyl sulfoxide layer was evaporated. The residue was taken up in 25 parts of water and 130 parts of dichloromethane. The separated organic layer was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane, methanol and methanol, saturated with ammonia, (92:4:4 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 20 parts of 4-methyl-2-pentanone. The product was filtered off and dried, yielding 4.4 parts (79.6%) of 5-[phenyl(1H-1,2,4-triazol-1-yl)methyl]-1H-benzotriazole; mp. 182.7° C. (compound 230).
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]=[C:9]1[CH:13]=[CH:12][C:11](=[O:14])[N:10]1[CH2:15][CH2:16][CH2:17][C:18]([NH:20][NH2:21])=[O:19].[C:22]([C:25]1[CH:80]=[CH:79][C:28]([O:29][CH2:30][CH2:31][O:32][C:33]2[CH:34]=[C:35]([CH2:59][O:60][C:61]3[C:62]([O:77][CH3:78])=[CH:63][C:64]4[C:70](=[O:71])[N:69]5[CH2:72][CH2:73][CH2:74][CH2:75][C@@H:68]5[CH:67]=[N:66][C:65]=4[CH:76]=3)[CH:36]=[C:37]([CH2:39][O:40][C:41]3[C:42]([O:57][CH3:58])=[CH:43][C:44]4[C:50](=[O:51])[N:49]5[CH2:52][CH2:53][CH2:54][CH2:55][C@@H:48]5[CH:47]=[N:46][C:45]=4[CH:56]=3)[CH:38]=2)=[CH:27][CH:26]=1)(=O)[CH3:23].C(Cl)(=O)C>C(Cl)Cl>[CH3:78][O:77][C:62]1[C:61]([O:60][CH2:59][C:35]2[CH:34]=[C:33]([CH:38]=[C:37]([CH2:39][O:40][C:41]3[C:42]([O:57][CH3:58])=[CH:43][C:44]4[C:50](=[O:51])[N:49]5[CH2:52][CH2:53][CH2:54][CH2:55][C@H:48]5[CH:47]=[N:46][C:45]=4[CH:56]=3)[CH:36]=2)[O:32][CH2:31][CH2:30][O:29][C:28]2[CH:79]=[CH:80][C:25](/[C:22](=[N:21]/[NH:20][C:18](=[O:19])[CH2:17][CH2:16][CH2:15][N:10]3[C:9](=[O:8])[CH:13]=[CH:12][C:11]3=[O:14])/[CH3:23])=[CH:26][CH:27]=2)=[CH:76][C:65]2[N:66]=[CH:67][C@@H:68]3[CH2:75][CH2:74][CH2:73][CH2:72][N:69]3[C:70](=[O:71])[C:64]=2[CH:63]=1
Reactant: NNC(=O)CCCN1C(=O)C=CC1=O
Reactant: COc1cc2c(cc1OCc1cc(COc3cc4c(cc3OC)C(=O)N3CCCC[C@@H]3C=N4)cc(OCCOc3ccc(C(C)=O)cc3)c1)N=C[C@H]1CCCCN1C2=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC(=O)Cl
Product: COc1cc2c(cc1OCc1cc(COc3cc4c(cc3OC)C(=O)N3CCCC[C@H]3C=N4)cc(OCCOc3ccc(/C(C)=N/NC(=O)CCCN4C(=O)C=CC4=O)cc3)c1)N=C[C@@H]1CCCCN1C2=O
Reaction time: 0.25 h
Yield: 61.4 %

Procedure:
4-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)butanehydrazide trifluoroacetic acid salt (246) (3 mg, 0.0096 mmol), (5Z,5′Z,6aR,6a′R)-3,3′-(5-(2-(4-Acetylphenoxy)ethoxy)-1,3-phenylene)bis(methylene)bis(oxy)bis(2-methoxy-7,8,9,10-tetrahydrobenzo[e]pyrido[1,2-a][1,4]diazepin-12(6aH)-one) (243) (7.5 mg, 0.0093 mmol) and 50 mg 4 A molecular sieves was stirred in 2 ml of dry 5% HAc in DCM (one day earlier dried by 4 A molecular sieves) for 2 h, neutralized with 0.5 ml of DIPEA, evaporated and purified on HPLC preparative C-18 column (Φ10 mm×200 mm column, flow rate 9 mL/min and a gradient solvent system going from 80:20 solvent A:B at time 0-5 min to 50:50 A:B at 15 min then to 30:70 A:B at 25 min until to 10:90 A:B at 30 min. Solvent A—water, solvent B—methanol/dioxane (2:1)) and lyophilized to afford a white solid 5.6 mg (61%) of the title compound. MS m/z+1066.3 (M+2CH3OH+Na).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]([OH:12])[C:9]([O-])=[O:10])[CH:5]=[CH:4][CH:3]=1.[K+].C1C=CC2N(O)N=[N:20][C:18]=2C=1.C(Cl)CCl.Cl.CN.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Br:1][C:2]1[N:7]=[C:6]([CH:8]([OH:12])[C:9]([NH:20][CH3:18])=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])C(O)c1cccc(Br)n1
Reactant: On1nnc2ccccc21
Agent: CN
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CNC(=O)C(O)c1cccc(Br)n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Potassium (6-bromopyridin-2-yl)(hydroxy)acetate (423 mg, 1.57 mmol), HOBT (600 mg, 3.91 mmol), EDC (750 mg, 3.91 mmol), and methylamine hydrochloride (529 mg, 7.83 mmol) were taken up in DMF (5.0 mL), and DIEA (684 μL, 3.91 mmol) was added. The reaction was stirred at room temperature for 6 hours, diluted with water, and extracted with 5:1 CH2Cl2:MeOH (2×). The combined organic layers were dried over MgSO4, filtered, and evaporated. Silica gel chromatography (40-100% EtOAc/hexanes) provided the title compound as a colorless solid.