Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[NH2:40][C:41]([NH:43][CH2:44][C@@H:45]([C:51](O)=[O:52])[NH:46][C:47]([O:49][CH3:50])=[O:48])=[O:42].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)CC)C>O1CCCC1>[CH3:50][O:49][C:47](=[O:48])[NH:46][C@@H:45]([CH2:44][NH:43][C:41]([NH2:40])=[O:42])[C:51](=[O:52])[NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@@H:3]([OH:32])[CH2:4][C@H:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)[NH:19][C:20](=[O:21])[C@H:22]([C:23]([CH3:26])([CH3:25])[CH3:24])[NH:27][C:28](=[O:31])[O:29][CH3:30]
Reactant: COC(=O)N[C@@H](CNC(N)=O)C(=O)O
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)N[C@@H](CNC(N)=O)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C
Temperature: 25 °C
Reaction time: 7 h
Yield: 56.2 %

Procedure:
A solution containing the product from Example 2C (0.025 g, 0.047 mmol) in tetrahydrofuran (0.5 mL) was treated with the product from Example 176A (0.014 g, 0.07 mmol), DEPBT (0.028 g, 0.094 mmol), and triethylamine (0.016 mL, 0.117 mmol), stirred at 25° C. for 7 hours, and partitioned between ethyl acetate and 10% NaHCO3 solution. The organic phase was washed with additional 10% NaHCO3 solution and brine, dried over MgSO4, filtered and concentrated. The product was purified by chromatography on silica gel eluting with 7% methanol/dichloromethane to give the title compound (0.019 g, 55% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.79 (s, 9H), 1.33-1.60 (m, 2H), 2.63-2.86 (m, 4H), 2.99-3.28 (m, 2H), 3.49 (s, 3H), 3.55 (s, 3H), 3.81 (d, J=9.56 Hz, 1H), 3.89-4.22 (m, 3H), 4.89 (d, J=6.62 Hz, 1H), 5.63 (s, 2H), 5.97 (s, 1H), 6.61 (d, 1H), 7.09-7.37 (m, 9H), 7.49 (d, J=9.19 Hz, 1H), 7.69-7.96 (m, 5H), 8.63 (d, J=4.41 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:19][CH2:20][CH3:21])[CH2:5][CH:6]([C:10]1[CH:15]=[CH:14][C:13]2[O:16][CH2:17][O:18][C:12]=2[CH:11]=1)[CH:7]([OH:9])[CH3:8])[CH3:2].[C:22](OC=C)(=[O:24])[CH3:23]>C(N(CC)CC)C>[C:22]([O:9][C@@H:7]([C@H:6]([C:10]1[CH:15]=[CH:14][C:13]2[O:16][CH2:17][O:18][C:12]=2[CH:11]=1)[CH2:5][CH:4]([O:19][CH2:20][CH3:21])[O:3][CH2:1][CH3:2])[CH3:8])(=[O:24])[CH3:23].[CH2:1]([O:3][CH:4]([O:19][CH2:20][CH3:21])[CH2:5][C@H:6]([C:10]1[CH:15]=[CH:14][C:13]2[O:16][CH2:17][O:18][C:12]=2[CH:11]=1)[C@@H:7]([OH:9])[CH3:8])[CH3:2]
Reactant: CCOC(CC(c1ccc2c(c1)OCO2)C(C)O)OCC
Reactant: C=COC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(C[C@@H](c1ccc2c(c1)OCO2)[C@@H](C)OC(C)=O)OCC
Product: CCOC(C[C@H](c1ccc2c(c1)OCO2)[C@H](C)O)OCC
Temperature: 30 °C
Reaction time: 16 h

Procedure:
To 31.98 g of (2RS,3SR)-5,5-diethoxy-3-(3,4-methylenedioxyphenyl)pentan-2-ol in 320 ml of vinyl acetate, 15.1 ml of triethylamine was added. The resulting reaction solution was stirred with 1.0 g of immobilized lipase (Toyozyme LIP) at 30° C. for 16 hours. After 0.9 g of immobilized lipase was further added, the solution was stirred at the same temperature for 46 hours. The insolubles were filtered off, and the filtrate was diluted with ethyl acetate, washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography [hexane/ethyl acetate=5/1→1/1] to give 18.40 g of (2R,3S)-2-acetoxy-5,5-diethoxy-3-(3,4-methylenedioxyphenyl)pentane and 16.05 g of the title compound as colorless oily substances.
Reaction SMILES: [C:1]([N:8]1[CH2:15][C@@H:14]([N:16]([C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C@H:17]2[CH2:22][CH2:21][C@@H:20]([CH3:23])[CH2:19][CH2:18]2)[CH2:13][C@H:9]1[C:10](O)=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(OC(Cl)=O)C.O.[NH3:37]>C1COCC1>[C:1]([N:8]1[CH2:15][C@@H:14]([N:16]([C:24](=[O:29])[C:25]([CH3:26])([CH3:28])[CH3:27])[C@H:17]2[CH2:22][CH2:21][C@@H:20]([CH3:23])[CH2:19][CH2:18]2)[CH2:13][C@H:9]1[C:10]([NH2:37])=[O:11])([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2]
Reactant: N
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N(C(=O)C(C)(C)C)[C@H]2CC[C@@H](C)CC2)C[C@H]1C(=O)O
Agent: CCOC(=O)Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](N(C(=O)C(C)(C)C)[C@H]2CC[C@@H](C)CC2)C[C@H]1C(N)=O
Reaction time: 1 h

Procedure:
To a solution of (4S)-1-BOC-4-[(2,2-dimethylpropanoyl)(cis-4-methyl-cyclohexyl)amino]-L-proline (0.83 g, 2.05 mmol) prepared in Step C in THF was added dropwise TEA (0.32 ml, 2.27 mmol). Then, ethylchloroformate (0.24 g, 2.27 mmol) was slowly added dropwise at 0° C., and the reaction solution was stirred at the same temperature for 1 h. 28% Ammonia water (1 equivalent) was slowly added dropwise at 0° C., and stirred at the same temperature for additional 1 h. After the reaction finished, the reaction mixture was concentrated in vacuo, and extracted with EtOAC. The organic extracts were washed with brine, dried over MgSO4, concentrated in vacuo, and purified by column chromatography (eluent: EtOAc/Hex=2/1) to give the title compound (0.62 g, 74%).
Reaction SMILES: BrC1C=CC(S(O[CH:12]2[CH2:25][N:24]3[C:15](=[N:16][C:17]4[C:22]([C:23]3=[O:26])=[CH:21][CH:20]=[C:19]([Br:27])[CH:18]=4)[CH2:14][CH2:13]2)(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>CO.O>[Br:27][C:19]1[CH:20]=[CH:21][C:22]2[C:23](=[O:26])[N:24]3[CH2:25][CH:12]4[CH2:13][CH:14]4[C:15]3=[N:16][C:17]=2[CH:18]=1
Reactant: O=c1c2ccc(Br)cc2nc2n1CC(OS(=O)(=O)c1ccc(Br)cc1)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=c1c2ccc(Br)cc2nc2n1CC1CC21
Temperature: 25 °C

Procedure:
A solution of 3-bromo-11-oxo-7,8,9,11-tetrahydro-6H-pyrido[2,1-b]quinazolin-8-yl 4-bromobenzenesulfonate (0.5 g, 0.98 mmol, 1.1 equiv) and K2CO3 in MeOH (100 mL) was stirred at reflux for two hours. After it was cooled to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over Na2SO4. After filtration and concentration, the residue was purified by silica gel chromatography to give the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20](Cl)(=[O:22])=[O:21]>CN(C1C=CN=CC=1)C>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2)(=[O:22])=[O:21]
Reactant: Nc1cccc2cccnc12
Reactant: COc1ccccc1S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Product: COc1ccccc1S(=O)(=O)Nc1cccc2cccnc12
Yield: 57.6 %

Procedure:
In the similar fashion using route 14 general procedure 27, 8-aminoquinoline (200 mg, 1.38 mmol), 2-methoxybenzenesulfonyl chloride (280 mg, 1.38 mmol) and DMAP (cat.) gave the title compound (250 mg, 58%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:14]=[CH:13][NH:12][N:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C([NH:22][C@@H:23]([CH2:26][CH3:27])[CH2:24]O)(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[NH2:22][C@@H:23]([CH2:26][CH3:27])[CH2:24][N:12]1[CH:13]=[CH:14][C:10]([C:8]2[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[CH:9]=2)=[N:11]1
Reactant: N#Cc1ccc(-c2cc[nH]n2)cc1Cl
Reactant: CC[C@@H](CO)NC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
2-Chloro-4-(1H-pyrazol-3-yl)benzonitrile (1.06 g, 4.40 mmol), N-Boc-(S)-(−)-2-amino-1-butanol (1.0 g, 5.28 mmol) and triphenylphosphine (1.73 g, 6.61 mmol) were dissolved in 15 ml of dry THF under nitrogen atmosphere. DIAD (1.73 ml; 8.81 mmol) was added slowly by syringe to cooled (0° C.) reaction mixture. After being stirred overnight at RT, the reaction mixture was evaporated to dryness. The evaporation residue was dissolved in 20 ml of 10% HCl (g)/EtOH-solution and stirred at RT overnight to induce Boc-deprotection. Solvents were evaporated and the evaporation residue was taken up in water and brine. Thus obtained solution was washed twice with DCM, made alkaline (pH˜12) by adding 2 M NaOH-solution, and extracted twice with DCM. The latter organic extracts were combined, dried over Na2SO4, filtered and evaporated to give 568 mg (47%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ0.87-0.94 (m, 3H), 1.10-1.45 (m, 2H), 2.97-3.05 (m. 1H), 4.01 (dd, 1H), 4.13 (dd, 1H), 4.68-4.86 (m, 1H), 6.97 (d, 1H), 7.86 (d, 1H), 7.95 (dd, 1H), 7.97 (dd, 1H), 8.10-8.12 (m, 1H). MS [M+1]: m/z [274.8+1].
Reaction SMILES: C[O-].[Na+].[Br:4][C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([CH3:15])[CH:14]=1)[N:11]=[C:10](Cl)[C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1)=[C:8]2[Cl:24].[C:25]([O-])(O)=[O:26].[Na+]>C1(C)C=CC=CC=1>[Br:4][C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([CH3:15])[CH:14]=1)[N:11]=[C:10]([O:26][CH3:25])[C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1)=[C:8]2[Cl:24]
Reactant: O=C([O-])O
Reactant: Cc1cc(Br)cc2c(Cl)c(-c3cccc(F)c3)c(Cl)nc12
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1nc2c(C)cc(Br)cc2c(Cl)c1-c1cccc(F)c1
Temperature: 100 °C

Procedure:
Sodium methoxide (4.29 g, 79.5 mmol) was added to a suspension of 6-bromo-2,4-dichloro-3-(3-fluorophenyl)-8-methylquinoline (3.06 g, 7.95 mmol, Intermediate 50, step c) in toluene (30 mL) in a pressure tube. The vessel was sealed and was heated in a 100° C. oil bath for 24 hours. To the mixture was added 10 wt. % aqueous NaHCO3 (60 mL), the mixture was stirred for several minutes, and the phases were separated. The organic phase was washed once with saturated aqueous NaCl. The organic phase was dried (Na2SO4), filtered, and concentrated to yield the title compound as a light yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][CH2:12][CH:11]2[C:15]([OH:17])=[O:16])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)(Cl)=O.[CH3:22]O>>[CH3:22][O:16][C:15]([CH:11]1[CH2:12][CH2:13][CH2:14][N:10]1[C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[O:17]
Reactant: CO
Reactant: O=C(O)C1CCCN1c1ccc([N+](=O)[O-])cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)C1CCCN1c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
A solution of 1-(4-nitro-phenyl)-pyrrolidine-2-carboxylic acid (0.75 g, 3.17 mmol) in methanol (20 ml) was cooled to 0° C. Thionyl chloride (0.71 ml, 9.51 mmol) was added dropwise and then the reaction mixture was stirred at room temperature overnight. The reaction mixture was evaporated to dryness and then diluted with dichloromethane. The organic layer was washed with bicarbonate solution, water and dried. Evaporation to dryness yielded 1-(4-nitrophenyl)-pyrrolidine-2-carboxylic acid methyl ester (0.58 g, 73%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:22])([CH3:21])[C:6]=2[CH:23]=1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34](O)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([O:1][C:2]2[CH:3]=[CH:4][C:5]3[C:17](=[O:18])[C:16]4[C:15]5[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=5)[NH:9][C:8]=4[C:7]([CH3:21])([CH3:22])[C:6]=3[CH:23]=2)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(c2)C(C)(C)c2[nH]c4cc(C#N)ccc4c2C3=O)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
8-Hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound A6, 30 mg, 0.099 mmol) was dissolved in THF (1 mL), added with 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (40 mg, 2 eq.), triphenylphosphine (52 mg, 2 eq.), and diisopropyl azodicarboxlyate (43 μL, 2 eq.) in order, and stirred at room temperature for 4 hr. The reaction solution was poured to water, and then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (37 mg, 76%).
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10](Cl)(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.[CH3:14][O:15][C:16](=[O:25])[C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[NH2:24]>>[CH3:14][O:15][C:16](=[O:25])[C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[NH:24][S:10]([C:6]1[C:3]2=[N:4][S:5][N:1]=[C:2]2[CH:9]=[CH:8][CH:7]=1)(=[O:12])=[O:11]
Reactant: COC(=O)c1cc(Cl)ccc1N
Reactant: O=S(=O)(Cl)c1cccc2nsnc12
Product: COC(=O)c1cc(Cl)ccc1NS(=O)(=O)c1cccc2nsnc12
Yield: 75 %

Procedure:
The title compound (1.56 g, 75%) was prepared from benzo[1,2,5]thiadiazole-4-sulfonyl chloride and 2-amino-5-chloro-benzoic acid methyl ester as in Example 1, Part A. HPLC: RT=10.77 min. MS (ESI+): mass calcd. for C14H10ClN3O4S2, 382.98; m/z found, 406 [M+Na]+. 1H NMR (500 MHz, CDCl3): 11.16 (s, 1H), 8.35 (dd, J=7.0, 1.0, 1H), 8.22 (dd, J=8.8, 1.0, 1H), 7.82 (d, J=2.5, 1H), 7.72-7.68 (m, 2H), 7.34 (dd, J=9.0, 2.5, 1H), 3.92 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[Br-].[NH4+:11].N>>[BrH:1].[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[NH:11])[NH2:7])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(Br)cc1
Reactant: [NH4+]
Agent: N
Agent: [Br-]
Product: Br
Product: N=C(N)c1ccc(Br)cc1

Procedure:
In an autoclave, 4-bromobenzonitrile (36.4 g, 200 mmol), ammonium bromide (39.2 g, 400 mmol) and ammonia gas (34.0 g, 2 mol) are heated to 140-150° C. under autogenous pressure for 9 h. The contents of the autoclave are concentrated and extracted by stirring with ethanol. The residue is filtered off and extracted again by stirring with ethanol. The extracts are combined and concentrated to about 100 ml. The precipitated solid is filtered off with suction, washed with ethanol and dried.
Reaction SMILES: [F:1][C:2]([F:50])([F:49])[C:3]1[CH:4]=[C:5]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[N:34]([C:37](=[O:41])[CH2:38][CH2:39][CH3:40])[CH2:35][CH3:36])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:10][N:9]=1.[OH-].[Na+].C(OCC)(=O)C>C(O)C>[F:50][C:2]([F:1])([F:49])[C:3]1[CH:4]=[C:5]([CH:42]=[C:43]([C:45]([F:46])([F:47])[F:48])[CH:44]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[N:34]([C:37](=[O:41])[CH2:38][CH2:39][CH3:40])[CH2:35][CH3:36])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:12][N:13]=1
Reactant: CCCC(=O)N(CC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)OCC)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCC(=O)N(CC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)O)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
Ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(butyryl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (78 mg) is dissolved in ethanol (1 ml) and thereto is added a 2N-aqueous sodium hydroxide solution (162 μl) and the mixture is stirred at room temperature for 3 hours. Thereto are added ethyl acetate and a 1N-hydrochloric acid, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(butyryl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid (66 mg). The resulting carboxylic acid is dissolved in ethanol (0.5 ml), and thereto is added 2N-aqueous sodium hydroxide solution (47 μl) and the reaction solution is concentrated under reduced pressure to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(butyryl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid sodium salt (68 mg). MS (m/z): 693 [M−Na]−
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].Cl>C(O)C>[CH2:13]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCc1ccccc1
Reactant: COC(=O)Cc1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COC(=O)Cc1ccc(OCc2ccccc2)cc1

Procedure:
Benzyl ethers may conveniently be used to protect --YH groups. For example, methyl 4-hydroxyphenylacetate (0.2 mol) is heated at reflux with 25 g benzyl chloride (0.2 mol) and 25 g K2CO3 (0.2 mol) in 100 ml ethanol. The product is added to dilute aqueous HCl, extracted with ether, and purified by silica gel chromatography to yield methyl 4-benzyloxyphenylacetate (7).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[CH3:29][O:30][C:31](=[O:51])[C@H:32]([NH:42][CH2:43][C:44]1[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=1)[CH2:33][O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>O1CCCC1.C(OCC)(=O)C>[CH3:29][O:30][C:31](=[O:51])[C@H:32]([N:42]([CH2:43][C:44]1[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=1)[C:11]([C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH3:10])=[O:13])[CH2:33][O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@@H](COCc1ccccc1)NCc1ccc(F)cc1
Agent: CC(C)COC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COC(=O)[C@@H](COCc1ccccc1)N(Cc1ccc(F)cc1)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 62.3 %

Procedure:
To a solution of N-t-butoxycarbonyl-D-alanine (5.6 g, 30 mmol, [α]D+23° (c=2, CH3CO2H)) in anhydrous tetrahydrofuran (150 mL) under N2 at 0° C. was added N-methylmorpholine (3.0 g, 30 mmol), followed by the addition of isobutylchloroformate (3.7 mL, 30 mmol), resulting in the formation of a white solid. The resulting suspension was stirred at 0° C. for 15 minutes, and then at ambient temperature for 1 hour. A solution of (2R)-3-benzyloxy-2-(N-(4-fluorobenzyl)-amino)propanoic acid methyl ester (7.5 g, 24 mmol, in 50 mL of anhydrous tetrahydrofuran) was added to the mixture and the resulting mixture was stirred at ambient temperature. After 15 hours, the mixture was filtered through Celite (tetrahydrofuran). The filtrate was concentrated in vacuo to afford a yellow liquid, which was dissolved in ethyl acetate, washed with water and then with brine. The organic phase was separated then dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel afforded 7.3 g (63% yield) of (2R)-3-benzyloxy-2-(N-(4-fluorobenzyl)-N-(((1S)-1-(t-butoxy-carbonylamino)ethyl)carbonyl)amino)propanoic acid methyl ester, a compound of formula (Q), as a clear oil; NMR (CDCl3) 7.4-7.2 (m, 7), 7.0 (dd, 2), 5.3 (d, 2), 4.9-4.3 (m, 5), 4.1-3.7 (m, 4), 1.6 (s, 9), 1.0 (d, 3) ppm.
Reaction SMILES: CC(O[C:6](=[O:20])[NH:7][C@@H:8]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([S:15]([CH3:18])(=[O:17])=[O:16])[C:9]1=[O:19])(C)C.C(O)(C(F)(F)F)=O.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+].[Cl:45][C:46]1[CH:55]=[C:54]2[C:49]([C:50]([N:57]3[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]3)=[CH:51][C:52]([NH2:56])=[N:53]2)=[CH:48][CH:47]=1>>[NH2:56][C:52]1[CH:51]=[C:50]([N:57]2[CH2:58][CH2:59][N:60]([C:6]([NH:7][C@H:8]3[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([S:15]([CH3:18])(=[O:16])=[O:17])[C:9]3=[O:19])=[O:20])[CH2:61][CH2:62]2)[C:49]2[C:54](=[CH:55][C:46]([Cl:45])=[CH:47][CH:48]=2)[N:53]=1
Reactant: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCCN(S(C)(=O)=O)C1=O
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N1CCCC[C@H](NC(=O)N2CCN(c3cc(N)nc4cc(Cl)ccc34)CC2)C1=O

Procedure:
As described for example 213, [(3R)-hexahydro-1-(methylsulfonyl)-2-oxo-1H-azepin-3-yl]-carbamic acid-1,1-dimethylethyl ester, TFA, triphosgene, NaHCO3 (sat.), and 7-chloro-4-(1-piperazinyl)-2-quinolinamine are reacted to afford the product as a light yellow solid. LC-MS: 495 (M++1). 1H NMR (CDCl3) δ 1.52 (m, 1H), 1.70 (m, 1H), 1.86 (m, 1H), 1.95˜2.05 (m, 2H), 2.15 (m, 1H), 3.09 (m, 4H), 3.45 (s, 3H), 3.48 (m, 1H), 3.65 (m, 4H), 4.45 (m, 1H), 4.81 (m, 1H), 5.17 (br.s, 2H), 5.95 (d, 1H), 6.15 (s, 1H), 7.15 (dd, 1H), 7.60 (d, 1H), 7.69 (d, 1H).
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([NH:15][NH2:16])=[O:14])(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([OH:30])=[C:25]([C:27](=O)[CH3:28])[CH:26]=1>CO.C(O)(=O)C>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([OH:30])=[C:25](/[C:27](=[N:16]/[NH:15][C:13](=[O:14])[C:12]2[CH:17]=[CH:18][CH:19]=[C:10]([S:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)(=[O:8])=[O:9])[CH:11]=2)/[CH3:28])[CH:26]=1
Reactant: CC(=O)c1cc(Cl)ccc1O
Reactant: NNC(=O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Solvent: CC(=O)O
Solvent: CO
Product: C/C(=N\NC(=O)c1cccc(S(=O)(=O)N2CCCCC2)c1)c1cc(Cl)ccc1O
Temperature: 120 °C
Yield: 54.1 %

Procedure:
3-(piperidin-1-ylsulfonyl)benzohydrazide (65 mg, 0.229 mmol) and 1-(5-chloro-2-hydroxyphenyl)ethanone (39.1 mg, 0.229 mmol) was dissolved in methanol (Volume: 4 ml) in the presence of acetic acid as a catalyst and then the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. Reaction was monitored by TLC. After completion of the reaction, following cooling, the solvent was removed by vacuum and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) afforded the product (E)-N′-(1-(5-chloro-2-hydroxyphenyl)ethylidene)-3-(piperidin-1-ylsulfonyl)benzohydrazide (55 mg, 0.124 mmol, 53.9% yield) as a solid. 1H NMR (CDCl3, 400 MHz): δ 8.09 (m, 2H), 7.85 (d, 1H, J=8.0 Hz), 7.62 (t, 1H, J=8.0 Hz), 7.41 (d, 1H, J=2.4 Hz), 7.22 (d, 1H, J=8.0 Hz), 6.93 (d, 1H, J=8.8 Hz), 2.97 (m, 4H), 2.41 (s, 3H), 1.61 (m, 4H), 1.40 (m, 2H). Mass [M+H]+: 436.9
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[C:21]([N+:23]([O-])=O)[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:13])[CH:6]=1.[Cl-].[NH4+].O.C(OCC)(=O)C>C(O)C.[Fe]>[NH2:23][C:21]1[CH:20]=[CH:19][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=[O:13])[CH:6]=2)=[C:2]([CH3:1])[CH:22]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1Oc1ccnc(NC(=O)N2CCCC2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc(N)ccc1Oc1ccnc(NC(=O)N2CCCC2)c1
Temperature: 90 °C
Yield: 66 %

Procedure:
To a solution of pyrrolidine-1-carboxylic acid [4-(2-methyl-4-nitrophenoxy)pyridin-2-yl]amide (775 mg) in ethanol (50 ml) were added electrolytic iron powder (505 mg), ammonium chloride (967 mg) and water (10 ml), followed by stirring to heat at 90° C. for 30 min. The reaction mixture was cooled down to room temperature, and filtered to remove an insoluble portion, which was then washed with water and N,N-dimethylformamide in this order. The filtrate was concentrated under a reduced pressure to give a residue, which was partitioned between ethyl acetate (100 ml) and water (100 ml). The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, to which ethyl acetate (10 ml) was added, followed by allowing to stand at room temperature. After a solid precipitated, diethyl ether (30 ml) was added thereto, followed by stirring at room temperature for 2 hrs. The solid was filtered off, and dried under aeration to provide the titled compound (467 mg, 66.2%) as powder.