Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[N:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]([CH2:28][CH2:29][CH2:30][OH:31])[CH2:20][CH2:21][CH2:22][C:23]([O:25]CC)=[O:24])=[CH:15][CH:14]=1.[OH-].[K+].C(O)(=O)C>C1COCC1.O.C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[N:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]([CH2:28][CH2:29][CH2:30][OH:31])[CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:17][CH:18]=1
Reactant: CCOC(=O)CCCN(CCCO)c1ccc(N=Nc2ccc([N+](=O)[O-])cc2Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)CCCN(CCCO)c1ccc(N=Nc2ccc([N+](=O)[O-])cc2Cl)cc1
Temperature: 4 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 20 (4.48 g, 10 mmole) in 40 mL of THF added 40 mL of ethanol followed by a solution of KOH (0.84 g, 15 mmol) in 20 mL of water and 20 mL of ethanol. The mixture is stirred overnight and concentrated. The residue suspended in 125 mL of water, treated with 2.6 mL (˜3 eqv.) of acetic acid, and cooled to 4° C. The resulting solid is filtered off, washed with water, and dried. Yield is quantitative. 1H NMR (DMSO-d6) δ 8.42 (d, J=2.5 Hz, aromatic proton, 1H), 8.23 (dd, J1=9 Hz, J2=2.5 Hz, aromatic proton, 1H), 7.82 (d, J=9 Hz, 2H), 7.90 (d, J=9 Hz, 1H), 7.03 (d, J=9 Hz, aromatic protons, 2H), 4.8 (br s, OH, 1H), 3.5 (m, aliphatic protons, 6H), 1.86 (t, J=6 Hz, aliphatic protons, 2H), 1.72 (m, aliphatic protons, 4H).
Reaction SMILES: [CH3:1][O:2][CH:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:4]([CH:6]1[C:11](=O)[CH2:10][CH2:9][O:8][CH2:7]1)=O.[CH3:19][C:20]1[N:21]([C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH2:34])=[NH:33])=[CH:27][CH:26]=2)[CH:22]=[CH:23][N:24]=1.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>CCO.O>[CH3:1][O:2][CH:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:4]1[C:6]2[CH2:7][O:8][CH2:9][CH2:10][C:11]=2[N:34]=[C:32]([NH:31][C:28]2[CH:29]=[CH:30][C:25]([N:21]3[CH:22]=[CH:23][N:24]=[C:20]3[CH3:19])=[CH:26][CH:27]=2)[N:33]=1
Reactant: COC(C(=O)C1COCCC1=O)c1ccccc1
Reactant: Cc1nccn1-c1ccc(NC(=N)N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: COC(c1ccccc1)c1nc(Nc2ccc(-n3ccnc3C)cc2)nc2c1COCC2
Temperature: 50 °C
Yield: 5.8 %

Procedure:
3-(2-Methoxy-2-phenylacetyl)dihydro-2H-pyran-4(3H)-one (100 mg, 0.40 mmol), 1-(4-(2-methyl-1H-imidazol-1-yl)phenyl)guanidine (Example 41c) (87 mg, 0.40 mmol) and potassium carbonate (55.7 mg, 0.40 mmol) was slurrified in EtOH (4 mL) and heated to 50° C. for 15 h. DCM and water were added. The organic phase was separated, dried with MgSO4 concentrated and purified by preparative HPLC yielding 4-(methoxy(phenyl)methyl)-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-amine (10.0 mg, 5.7%). MS (ES+) m/z 428.1 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[CH2:17][N:16]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:14][CH:13]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]2[CH2:13][CH2:14][CH2:15][N:16]([CH2:18][CH2:19][CH3:20])[CH2:17]2)[CH:6]=[CH:7][C:8]=1[NH2:9]
Reactant: CCCN1CCC=C(c2ccc([N+](=O)[O-])c(OC)c2)C1
Solvent: CCOC(C)=O
Product: CCCN1CCCC(c2ccc(N)c(OC)c2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.9 %

Procedure:
In a pressure vessel was placed 5-[3-(methyloxy)-4-nitrophenyl]-1-propyl-1,2,3,6-tetrahydropyridine (Intermediate B11, 4.1 g, 15.0 mmol) in Ethyl acetate (100 mL). The solution was bubbled with nitrogen for 15 min before the addition of 10% Pd/C (0.5 g). The reaction was stirred at RT for 12 h under 60 psi of H2. After releasing H2 pressure, the mixture was filtered through celite, and the filtrate was concentrated and purified by silica gel chromatography to afford 2-(methyloxy)-4-(1-propyl-3-piperidinyl)aniline (3.5 g, 96% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.82 (t, J=7.3 Hz, 3 H), 1.27-1.45 (m, 3 H), 1.45-1.58 (m, 1 H), 1.61-1.69 (m, 1 H), 1.69-1.77 (m, 1 H), 1.77-1.89 (m, 2 H), 2.16-2.26 (m, 2 H), 2.50-2.58 (m, 1 H), 2.75-2.88 (m, 2 H), 3.72 (s, 3 H), 4.47 (s, 2 H), 6.52 (d, J=0.9 Hz, 2 H), 6.65 (s, 1 H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:37])[C:8]2[CH:13]=[N:12][C:11]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21](=[O:25])[N:22]([CH3:24])[CH3:23])[CH:16]=3)=[N:10][C:9]=2[N:26]([C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[CH2:33][CH2:32][CH2:31]3)[CH:27]=1)=O)C.[CH2:38]([NH2:40])[CH3:39]>CO>[CH2:38]([NH:40][C:4]([C:6]1[C:7](=[O:37])[C:8]2[CH:13]=[N:12][C:11]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21](=[O:25])[N:22]([CH3:24])[CH3:23])[CH:16]=3)=[N:10][C:9]=2[N:26]([C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[CH2:33][CH2:32][CH2:31]3)[CH:27]=1)=[O:3])[CH3:39]
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3cccc(C(=O)N(C)C)c3)ncc2c1=O
Reactant: CCN
Solvent: CO
Product: CCNC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3cccc(C(=O)N(C)C)c3)ncc2c1=O
Temperature: 80 °C
Reaction time: 16 h
Yield: 42.3 %

Procedure:
2-(3-Dimethylcarbamoyl-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (5.2 mg, 0.010 mmol) was dissolved in MeOH (1 mL) and ethylamine (1 mL of 1.0 M solution in THF, 1.0 mmol) was added and the reaction mixture was heated at 80° C. After 16 h, the solution was cooled to rt and purified by preparative HPLC (C-18 column, 32 mL/min 5-100% MeCN/H2O gradient over 15 min) and lyophilized to provide 2.1 mg of 2-(3-dimethylcarbamoyl-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethylamide. 1H NMR (TFA salt) (400 MHz, CDCl3) δ (ppm): 9.64 (s, 1H), 9.32 (s, 1H), 8.77 (s, 1H), 7.51 (dd, 1H, J=2.3 Hz, J=9.3 Hz), 7.34 (d, 1H, J=7.8 Hz), 7.17-7.19 (m, 3H), 7.11 (dd, 1H, J=2.0 Hz, J=8.0 Hz), 6.99 (br. S, 1H), 3.44 (dq, 2H, J=5.8 Hz, J=7.3 Hz), 2.86-3.05 (m, 10H), 2.11-2.19 (m, 2H), 1.21 (t, 1H, J=7.3 Hz). Mass Spectrum (LCMS, ESI pos.) Calcd. for C28H28N6O3: 496.22, Found: 497.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:16]([CH3:24])=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:7][CH:6]=2.[Br:25]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:25][CH2:24][C:16]1[N:4]2[C:5]3[C:10]([N:11]=[C:2]([Cl:1])[C:3]2=[N:18][C:17]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:9][C:8]([C:12]([F:15])([F:13])[F:14])=[CH:7][CH:6]=3
Reactant: CCOC(=O)c1nc2c(Cl)nc3cc(C(F)(F)F)ccc3n2c1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1nc2c(Cl)nc3cc(C(F)(F)F)ccc3n2c1CBr
Yield: 90.5 %

Procedure:
A mixture of 4-chloro-2-ethoxycarbonyl-1-methyl-7-trifluoromethylimidazo[1,2-a]quinoxaline (830 g, 232 mmol), N-bromosuccinimide (68,0 g, 382 mmol) and 2,2'-azobis(2-methylpropionitrile)(200 mg, 1.2 mmol) in tetrachloromethane (1.5 l) was heated at reflux for 18 h, allowed to cool and the product collected by filtration. The product was dissolved in dichloromethane (2 l) and washed with water, dried (MgSO4), followed by purification with silica gel 60 (1 g). The organic phase was filtered and evaporated in vacuo. The residue was suspended in petroleum ether to yield 91.7 g (91%) of 1-bromomethyl-4-chloro-2-ethoxycarbonyl-7-trifluoromethyl-imidazo[1,2-a]quinoxaline which was collected by filtration. M.p. 196°-198° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[C:4]([Cl:17])[CH:3]=1.[F:18][C:19]1[CH:20]=[CH:21][C:22]([O:28][CH3:29])=[C:23](B(O)O)[CH:24]=1>>[Cl:17][C:4]1[CH:3]=[C:2]([C:21]2[CH:20]=[C:19]([F:18])[CH:24]=[CH:23][C:22]=2[O:28][CH3:29])[CH:7]=[CH:6][C:5]=1[S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(c1ccccc1)c1ccc(Br)cc1Cl
Reactant: COc1ccc(F)cc1B(O)O
Product: COc1ccc(F)cc1-c1ccc(S(=O)(=O)c2ccccc2)c(Cl)c1

Procedure:
The subtitle compound was prepared by the method of example 2 step (ii) using the product of step (i) and 5-fluoro-2-methoxybenzene boronic acid.
Reaction SMILES: [CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:2]([CH3:4])[CH3:3].[C:25]([O:29][C:30]([NH:32][C@H:33]([C:49](O)=[O:50])[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[CH:37][CH:36]=1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[CH3:24][C:21]1[CH:22]=[CH:23][C:18]([S:15]([N:5]([C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:49]([C@@H:33]([NH:32][C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[CH2:34][C:35]2[CH:36]=[CH:37][C:38]([O:41][CH2:42][C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)=[CH:39][CH:40]=2)=[O:50])[CH2:1][CH:2]([CH3:3])[CH3:4])(=[O:17])=[O:16])=[CH:19][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCN)C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Product: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)[C@H](Cc2ccc(OCc3ccccc3)cc2)NC(=O)OC(C)(C)C)C(=O)O)cc1

Procedure:
The title compound was prepared from Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-L-lysine (100 mg, 0.29 mmol, example 1, step E) as described in general procedure Bc using commercially available Nα-tert-butoxycarbonyl-O-benzyl-L-tyrosine (111 mg, 0.3 mmol). The final product was triturated with ether to yield 145 mg (68%) of the desired material.
Reaction SMILES: CCCCCCCCCO[C:11]1[CH:16]=[CH:15][C:14]([N:17]=[N:18][C:19]2[CH:24]=[CH:23][C:22](OCCCCCCCCCOC(C=C)=O)=[CH:21][CH:20]=2)=[CH:13][CH:12]=1.N#N>O.C(Cl)(Cl)Cl>[N:17]([C:14]1[CH:13]=[CH:12][CH:11]=[CH:16][CH:15]=1)=[N:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C=CC(=O)OCCCCCCCCCOc1ccc(N=Nc2ccc(OCCCCCCCCC)cc2)cc1
Agent: N#N
Solvent: ClC(Cl)Cl
Solvent: O
Product: c1ccc(N=Nc2ccccc2)cc1
Temperature: 64 °C
Reaction time: 1 h

Procedure:
The polymer precursors A9AB9 and DA9AB along with the surfactant AC10COONa were used, with the structure of each shown in FIG. 3. The azobenzene nanoparticles were synthesized using a mini-emulsion process. Similar processes have been described in documents 12 through 14. To prepare the instant nanoparticle, 15 mg of surfactant AC10COONa was dissolved in 10 ml of water. 20 mol % of A9AB9 and 80 mol % of DA9AB were mixed with 2 w % 2,2′-azoisobutyronitrile (AIBN) in 2 g of chloroform. The solution was added drop by drop to the surfactant solution and stirred for 1 hour. The mixture was then sonicated in an ice bath for 2 minutes at 90% amplitude using an Ultrasonic Processor (ACE Glass, Inc) with a probe (Model LV261). The resulting mini-emulsion was stirred at room temperature with N2 bubbled into it for 15 min to remove oxygen. With continuous stirring and bubbling of N2, the emulsion was then heated in an oil bath at 64° C. for 6 hours to remove chloroform and promote polymerization. A nanocolloid suspension comprising the desired nanoparticles was obtained.
Reaction SMILES: [OH-].[Na+].[F:3][CH:4]([F:38])[O:5][C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH:9]3[NH:16][C:17]([C:19]3[CH:20]=[N:21][N:22]([C:28]4[CH:37]=[CH:36][C:31]([C:32]([O:34]C)=[O:33])=[CH:30][CH:29]=4)[C:23]=3[S:24][CH2:25][CH2:26][CH3:27])=[O:18])[CH2:7]1)[CH2:13]2>CO>[F:38][CH:4]([F:3])[O:5][C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH:9]3[NH:16][C:17]([C:19]3[CH:20]=[N:21][N:22]([C:28]4[CH:37]=[CH:36][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=4)[C:23]=3[S:24][CH2:25][CH2:26][CH3:27])=[O:18])[CH2:7]1)[CH2:13]2
Reactant: CCCSc1c(C(=O)NC2C3CC4CC2CC(OC(F)F)(C4)C3)cnn1-c1ccc(C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCSc1c(C(=O)NC2C3CC4CC2CC(OC(F)F)(C4)C3)cnn1-c1ccc(C(=O)O)cc1
Temperature: 20 °C
Reaction time: 18 h
Yield: 68.5 %

Procedure:
2M aqueous sodium hydroxide (2.050 mL, 4.10 mmol) was added in one portion to methyl 4-[4-[[5-(difluoromethoxy)-2-adamantyl]carbamoyl]-5-propylsulfanylpyrazol-1-yl]benzoate (Intermediate #95) (459 mg, 0.82 mmol) in methanol (10 mL). The resulting mixture was stirred at 20° C. for 18 hours and then a further 4 hours at 55° C. The reaction mixture was concentrated and diluted with water (50 mL), and washed with ether (20 mL). The aqueous solution was adjusted to pH 3 with 2M HCl and extracted with EtOAc (2×25 mL), and the combined extracts washed sequentially with water (2×20 mL) and saturated brine (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford 4-[4-[[5-(difluoromethoxy)-2-adamantyl]carbamoyl]-5-propylsulfanylpyrazol-1-yl]benzoic acid (284 mg, 63.5%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[C:22]([F:23])=[CH:21][C:15]3[NH:16][C:17](=[O:20])[CH2:18][O:19][C:14]=3[CH:13]=2)=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8].C([O-])([O-])=O.[K+].[K+].[CH2:30](Br)[C:31]#[CH:32]>CS(C)=O.O>[Cl:1][C:2]1[C:3]([C:12]2[C:22]([F:23])=[CH:21][C:15]3[N:16]([CH2:32][C:31]#[CH:30])[C:17](=[O:20])[CH2:18][O:19][C:14]=3[CH:13]=2)=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:9])([F:8])[F:10]
Reactant: C#CCBr
Reactant: Cn1nc(-c2cc3c(cc2F)NC(=O)CO3)c(Cl)c1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C#CCN1C(=O)COc2cc(-c3nn(C)c(C(F)(F)F)c3Cl)c(F)cc21
Temperature: 45 °C
Reaction time: 16 h
Yield: 90.4 %

Procedure:
At 25° C., 2.7 g (7.7 mmole) the product of step A, 1.1 g (8.0 mmole) K2CO3 and 0.9 mL (8.0 mmole) 80% propargyl bromide were slurried in 25 mL DMSO. The mixture was stirred at 45° C. for 16 hours. The mixture was cooled, diluted with 100 mL cold water and extracted four times with ethyl acetate. The ethyl acetate extracts were washed with brine, dried over anhydrous MgSO4 and stripped in vacuo. The residue was purified chromatographically using methylene chloride as the eluent to give 2.7 g (90%) of 7-(4-chloro-1-methyl-5-(trifluoromethyl)-1H -pyrazol-3-yl)-6-fluoro-4-(2-propynyl)-2H-1,4-benzoxazin-3(4H) -one as a white solid, mp 184° C.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:23])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:22])[C@H:17]([CH:19]([CH3:21])[CH3:20])[NH2:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:31]1([S:37](Cl)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl>[CH2:2]([O:9][C:10](=[O:23])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:22])[C@H:17]([CH:19]([CH3:21])[CH3:20])[NH:18][S:37]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:39])=[O:38])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[C@H](NS(=O)(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 90 %

Procedure:
L-valyl-L-proline benzylester hydrochloride (1.70 g, 5 mmole) was dissolved in methylene chloride (30 ml), and triethylamine (1.11 g, 11 mmole) was added thereto at -30° C. Methylene chloride (10 ml) solution of benzene sulfonyl chloride (0.86 g, 5 mmole) was added dropwise to the solution. The mixture was stirred for 1 hour at less than 0° C., and then for 5 hours at room temperature, and methylene chloride (60 ml) was added thereto. The solution was washed with aqueous 5% sodium bicarbonate (100 ml, twice), 1N aqueous hydrochloric acid (100 ml, twice) and water (100 ml) in the order given and dried over anhydrous magnesium sulfate. The solvent was stilled off under reduced pressure to obtain N-benzenesulfonyl-L-valyl-L-proline benzylester(yield: 2.00 g, 90.0%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=O)[C:19](=[N:27]O)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:14][CH:13]=1>N1C=CC=CC=1>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[NH:10][C:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=3)=[N:27][C:19]=2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:14][CH:13]=1
Reactant: NCc1ccc(CO)cc1
Reactant: CC(C)(C)OC(=O)C(=NO)C(=O)c1ccc(Cl)cc1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)c1nc(-c2ccc(CO)cc2)[nH]c1-c1ccc(Cl)cc1

Procedure:
4-(Hydroxymethyl)phenylmethylamine and tert-butyl 3-(4-chlorophenyl)-2-hydroxyimino-3-oxopropionate are dissolved in pyridine, and the mixture is treated in the same manner as in Starting Material Synthetic Example 170 to give the objective tert-butyl 5-(4-chlorophenyl)-2-(4-hydroxymethylphenyl)imidazole-4-carboxylate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:10]=1[O:11][CH2:12][C:13](OCC)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].CO.O>C1COCC1>[CH2:1]([O:8][C:9]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:10]=1[O:11][CH2:12][CH2:13][OH:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)COc1ccc([N+](=O)[O-])cc1OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=[N+]([O-])c1ccc(OCCO)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl (2-benzyloxy-4-nitrophenoxy)acetate (800 mg, 4.83 mmol) was dissolved in THF (50 ml); thereafter, sodium borohydride (457 mg, 12.1 mmol) was added and the mixture was heated to the reflux temperature. At the same temperature, methanol (5 ml) was slowly added dropwise over 30 min, followed by stirring at the reflux temperature for 30 min. The reaction solution was cooled to room temperature and water (10 ml) was added, followed by extraction with ethyl acetate (200 ml). The extracted organic layer was dried with magnesium sulfate and the solvent was evaporated; the resulting residue was purified by being subjected to column chromatography on silica gel using a 1:1 solvent system on n-hexane and ethyl acetate as an eluent. The fractions containing the product were collected and the solvent was evaporated to yield the end compound 2-(2-benzyloxy-4-nitrophenoxy)ethanol (400 ml).
Reaction SMILES: C([CH:6]1[CH:11]([CH2:12][CH2:13][C:14]([O:17][CH3:18])([CH3:16])[CH3:15])[CH2:10][CH2:9][CH2:8][C:7]1=[O:19])(OCC)=O.[OH-].[K+].CO>O>[CH3:18][O:17][C:14]([CH3:16])([CH3:15])[CH2:13][CH2:12][CH:11]1[CH2:10][CH2:9][CH2:8][C:7](=[O:19])[CH2:6]1
Reactant: CCOC(=O)C1C(=O)CCCC1CCC(C)(C)OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(C)(C)CCC1CCCC(=O)C1
Yield: 19.5 %

Procedure:
Crude 2-carbethoxy-3-(3-methoxy-3-methylbut-1-yl)cyclohexanone (7.0 g) of example 17 was added to a mixture of potassium hydroxide (3.0 g), methanol (50 mL) and water (50 mL) and heated at reflux 4.5 hours. The cooled mixture was extracted with hexane, the extracts were dried (Na2SO4) and concentrated to an oil which was purified by bulb to bulb distillation, airbath temperature 175~C., 0.1 mm Hg to yield 3-(3-methoxy-3-methylbut-1-yl)cyclohexanone (1.0 g); NMR (CDCl3)δ 1.2(s,6H), 1.2-1.5(m,5H), 1.6-1.8(m,2H), 1.9-2.1(m,3H), 2.2-2.4(m,3H), 3.2(s,3H); IR (neat) 2970, 2950, 1720, 1460, 1370, 1230, 1090 cm-1 ; MS (m/e) 41, 55, 73, 110, 133, 151, 183, 184.
Reaction SMILES: C([SiH](CC)CC)C.[CH3:8][C:9]1([CH3:23])[C:18](=O)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([S:20][CH3:21])[CH:16]=2)[NH:11][C:10]1=[O:22].C(=O)([O-])[O-].[K+].[K+]>FC(F)(F)C(O)=O>[CH3:8][C:9]1([CH3:23])[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([S:20][CH3:21])[CH:16]=2)[NH:11][C:10]1=[O:22]
Reactant: CSc1ccc2c(c1)C(=O)C(C)(C)C(=O)N2
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: CSc1ccc2c(c1)CC(C)(C)C(=O)N2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Triethylsilane (34.75 ml, 49.1 g, 0.042 mol) was added dropwise to a stirred solution of 3,3-dimethyl-6-methylthio-2,4(1H,3H)-quinolinedione (12.79 g, 0.054 mol) in trifluoroacetic acid (520 ml) under nitrogen at 60° C. The reaction was then allowed to cool slowly to room temperature and was stirred for 16 hr. The solvent was then evaporated in vacuo to afford a yellow residue. The residue was then poured into saturated potassium carbonate solution (200 ml). The product was extracted with ethyl acetate (3×150 ml). The organic extracts were combined, washed with water (200 ml), dried and concentrated in vacuo to afford 3,4-dihydro-3,3-dimethyl-6-methylthio-2(1H)-quinolinone as a yellow solid. Mp 154° C.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([Cl:26])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[N+:27]([O-])([O-:29])=[O:28].[K+]>S(=O)(=O)(O)O>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([Cl:26])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:25]=[CH:24][C:23]([N+:27]([O-:29])=[O:28])=[CH:22][CH:21]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: O=[N+]([O-])[O-]
Reactant: CCCCOC(=O)c1nc(Cl)c2ccc(Oc3ccccc3)cc2c1O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCCCOC(=O)c1nc(Cl)c2ccc(Oc3ccc([N+](=O)[O-])cc3)cc2c1O
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 45.9 %

Procedure:
200 mg of 1-Chloro-4-hydroxy-6-phenoxy-isoquinoline-3-carboxylic acid butyl ester, Example D-10 a, was dissolved in 3 ml of concentrated sulfuric acid. The reaction mixture was cooled to −20° C. and 60 mg of potassium nitrate was added slowly to the stirring solution. The reaction was kept between −10 to −20° C. while stirring for 15 min, and poured into ice-water. The aqueous mixture was extracted twice with ethyl acetate. The organic fractions were washed successively with saturated bicarbonate and brine solutions, dried over anhydrous magnesium sulfate, and concentrated to a residue under reduced pressure. The resultant solid was triturated with ethyl acetate followed by methanol to produce 103 mg of white solid; MS (+): m/z 417.07 (M+1).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[F:12][C:13]([F:19])([F:18])[C:14]([CH3:17])([NH2:16])[CH3:15].C(N(CC)CC)C>ClCCl>[Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:16][C:14]([CH3:17])([CH3:15])[C:13]([F:19])([F:18])[F:12])=[O:7]
Reactant: CC(C)(N)C(F)(F)F
Reactant: O=C(Cl)c1cccc(CCl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(NC(=O)c1cccc(CCl)c1)C(F)(F)F
Reaction time: 2 h
Yield: 46.4 %

Procedure:
3-(Chloromethyl)benzoyl chloride (38.5 mmol, 5.48 mL, 7.29 g) was dissolved in dichloromethane (100 mL) and stirred. To this was added a mixture of 1,1,1-trifluoro-2-methylpropan-2-amine (39.3 mmol, 5 g) and triethylamine (59.0 mmol, 8.22 mL, 5.97 g) (dropwise) and stirring continued for 2 hours. The reaction was diluted with dichloromethane and this organic mixture was washed with saturated sodium chloride, water, and saturated sodium chloride. The organic phase was dried with sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica chromatography (eluting with dichloromethane) to give the title compound (5 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[C:10](=[O:20])[N:11]([CH3:19])[C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=2)=[C:4]([F:21])[CH:3]=1.C1C(=O)N([Br:29])C(=O)C1.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[C:7]([CH2:8][Br:29])=[CH:6][C:5]([C:9]2[C:10](=[O:20])[N:11]([CH3:19])[C:12]([C:15]([F:16])([F:17])[F:18])=[CH:13][CH:14]=2)=[C:4]([F:21])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(-c2ccc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Cn1c(C(F)(F)F)ccc(-c2cc(CBr)c(Cl)cc2F)c1=O
Yield: 81.4 %

Procedure:
2.63 g (8.23 mmol) of 3-(4-chloro-2-fluoro-5-methylphenyl)-1-methyl-6-trifluoromethyl-2(1H)-pyridone and 1.46 g (8.23 mmol) of NBS were dissolved in 100 ml of carbon tetrachloride. Then, 0.27 g (1.67 mmol) of 2,2′-azobisisobutyronitrile was slowly added thereto with stirring under heating and refluxing. Then, the mixture was further reacted for 5 hours. After cooling, the insoluble substances were filtered off, and the organic layer was washed with water and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 2.67 g (yield: 81%) of the desired product. Melting point: 117-118° C.