Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6](Cl)=[C:5]([CH2:12][CH2:13][CH3:14])[N:4]=1)#[N:2].[C:15]1([OH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[Na+].O>CC(C)=O>[C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6]([O:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:5]([CH2:12][CH2:13][CH3:14])[N:4]=1)#[N:2]
Reactant: Oc1ccccc1
Reactant: CCCc1nc(C#N)c(C#N)nc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CCCc1nc(C#N)c(C#N)nc1Oc1ccccc1
Reaction time: 0.17 h
Yield: 56.8 %

Procedure:
2,3-Dicyano-5-chloro-6-n-propylpyrazine (0.207 g; 0.001 mole) was dissolved in 15 ml of acetone, and a solution prepared from 0.094 g (0.001 mole) of phenol, 0.040 g (0.001 mole) of sodium hydroxide, 0.7 ml of water and 5 ml of acetone was added dropwise over the period of 5 minutes. Then, the mixture was stirred at 5° to 10° C. for 10 minutes. The reaction mixture was worked up in the same way as in Example 9, and recrystallized from benzene to afford 0.150 g (yield 57%) of 2,3-dicyano-5-phenoxy-6-propylpyrazine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=2)=[C:6]([OH:8])[CH:7]=1.[CH2:18]([O:25][C:26](ON1C(=O)CCC1=O)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCCC1>[CH2:16]([C:13]1[CH:12]=[CH:11][C:10]([CH2:9][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:26](=[O:27])[O:25][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:7][C:6]=2[OH:8])=[CH:15][CH:14]=1)[CH3:17]
Reactant: CCc1ccc(Cc2ccc(N)cc2O)cc1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: C1CCOC1
Product: CCc1ccc(Cc2ccc(NC(=O)OCc3ccccc3)cc2O)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 100.6 %

Procedure:
To a solution of 5-amino-2-(4-ethylbenzyl)phenol (0.25 g) in tetrahydrofuran (10 mL) was added N-benzyloxycarbonyloxy-succinimide (0.41 g), and the mixture was stirred at room temperature for 22 hours. The reaction mixture was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=5/1) to give benzyl N-[4-(4-ethylbenzyl)-3-hydroxyphenyl]carbamate (0.40 g).
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1.[N+:13]([CH2:15][C:16]([N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:17])#[C-:14]>CO>[CH3:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([C@@H:9]2[O:10][CH:14]=[N:13][C@H:15]2[C:16]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])=[CH:7][CH:6]=1
Reactant: [C-]#[N+]CC(=O)N1CCCC1
Reactant: COc1ccc(C=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc([C@@H]2OC=N[C@H]2C(=O)N2CCCC2)cc1
Yield: 66.6 %

Procedure:
To a stirred and cooled (0° C.) solution of potassium hydroxide (0.37 g, 6.57 mmol) in methanol (30 mL) was added a mixture of 4-methoxy-benzaldehyde (0.88 mL, 7.23 mmol) and 2-isocyano-1-(pyrrolidin-1-yl)ethanone BLE 04098 (1.0 g, 6.57 mmol). The solution was stirred 4 h with continued cooling and then concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was combined with additional ethyl acetate extracts, washed with aqueous sodium chloride and dried over MgSO4. Concentration afforded a crude product as a glassy solid. Flash chromatography over silica (ethyl acetate) yielded to trans-(4,5-dihydro-5-(4-methoxyphenyl)oxazol-4-yl)(pyrrolidin-1-yl)methanone SLA 07074 as a pale yellow solid (1.2 g, 90.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][C:3]=1[OH:9].[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:18]=[C:19]([CH2:23][C:24]([OH:26])=O)[CH:20]=[CH:21][CH:22]=1)#[N:11].P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:33]N(C=O)C>>[Cl:1][C:2]1[CH:8]=[C:7]2[C:5](=[CH:4][C:3]=1[OH:9])[O:6][CH:33]=[C:23]([C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[O:16][CH2:15][CH2:14][CH2:13][CH2:12][C:10]#[N:11])[C:24]2=[O:26]
Reactant: Oc1ccc(Cl)c(O)c1
Reactant: N#CCCCCOc1cccc(CC(=O)O)c1
Reactant: CN(C)C=O
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: N#CCCCCOc1cccc(-c2coc3cc(O)c(Cl)cc3c2=O)c1
Yield: 59.1 %

Procedure:
This compound was synthesised in the same manner as described above. 4-Chlororesorcinol (0.37 g, 2.58 mmol), [3-(4-Cyano-butoxy)-phenyl]-acetic acid (0.6 g, 2.58 mmol), BF3Et2O (8 ml), PCl5 (0.81 g, 3.89 mmol), DMF (8 ml and 12 ml). The precipitate formed was filtered and re-crystallized from methanol to give 5-[3-(6-Chloro-7-hydroxy-4-oxo-4H-chromen-3-yl)-phenoxy]-pentanenitrile as a white solid (0.59 g, 59.1%); Rf 0.7 ethyl acetate/hexane (80/20)].
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:42]=[C:43]([CH2:47][CH2:48][O:49]S(C)(=O)=O)[CH:44]=[CH:45][CH:46]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:54]1[CH2:58][CH2:57][CH2:56][CH2:55]1.C1C[O:62]CC1>>[CH:48]([OH:49])=[O:62].[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][CH2:48][N:54]3[CH2:58][CH2:57][CH2:56][CH2:55]3)[CH:42]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(CCOS(C)(=O)=O)c4)c4ccccc43)cn12
Reactant: C1CCNC1
Reactant: C1CCOC1
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(CCN5CCCC5)c4)c4ccccc43)cn12
Product: O=CO

Procedure:
A solution of Intermediate 131d (44.5 mg, 0.06 mmol) and pyrrolidine (24.8 μL, 0.30 mmol) in THF (1 mL) was stirred at 60° C. for 20 h in a sealed tube. The mixture was concentrated in vacuo and the residue purified by MDAP (Method 7). The title product was isolated as an off-white solid (15 mg, 35%). LCMS (Method 5): Rt 3.70 min, ink 716.6 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.91 (3H, d, J=6.6 Hz), 1.28 (9H, s), 1.50 (2H, m), 1.61-1.72 (6H, m), 1.76-2.18 (6H, overlapped m), 2.53 (m, obscured by solvent), 2.72 (2H, m), 2.82 (2H, m), 2.90 (1H, m), 3.16 (1H, m, obscured by solvent), 3.31 (m, obscured by solvent), 4.82 (1H, m), 5.52 (1H, t, J=4.2 Hz), 6.33 (1H, s), 7.10 (1H, d, J=8.4 Hz), 7.19 (1H, dd, J=10.0, 2.0 Hz), 7.24-7.44 (8H, m), 7.64 (1H, m), 7.69 (1H, m), 8.14 (1H, s), 8.19 (1H, s).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[CH3:14][S-:15].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH3:14][S:15][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1ccc(Cl)nc1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1ccc(SC)nc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 40.2 %

Procedure:
To a solution of ethyl (6-chloropyridin-3-yl)acetate (10.7 g) in N,N-dimethylformamide (100 mL) was added sodium methanethiolate (11.3 g), and the mixture was stirred at room temperature for 23 hr. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=5:95-50:50, volume ratio) to give the title compound (4.55 g, yield 40%) as a colorless oil. MS: 212 (MH+).
Reaction SMILES: Cl([O-])=O.[Na+].P([O-])(O)(O)=[O:6].[Na+].CC(=CC)C.[C:16]([O:20][C:21]([N:23]1[CH2:26][CH:25]([CH2:27][O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH:35]=[O:36])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>O.O1CCOCC1>[C:16]([O:20][C:21]([N:23]1[CH2:26][CH:25]([CH2:27][O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]([OH:6])=[O:36])[CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: O=P([O-])(O)O
Reactant: CC(C)(C)OC(=O)N1CC(COc2ccccc2C=O)C1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC(COc2ccccc2C(=O)O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
A solution of sodium chlorite (1.37 g; 15.10 mmol; 5.5 eq.) and sodium dihydrogenphosphate (1.19 g; 9.89 mmol; 3.6 eq.) in water (8 mL) was added dropwise to a mixture of 2-methyl-2-butene (2.7 mL) and 3-(2-formyl-phenoxymethyl)-azetidine-1-carboxylic acid tert-butyl ester (800 mg; 2.75 mmol; 1 eq.) in 1,4-dioxane (8 mL) and the resulting mixture was stirred at room temperature for 1 hour. The 1,4-dioxane was evaporated in vacuo, water was added and the pH made acidic with 1M HCl. The precipitate was filtered off to afford the title compound (827 mg, 98%) as a white solid. HPLC (max plot) 100%; Rt 3.58 min. UPLC/MS: (MS−) 306.4 ([M−H]−).
Reaction SMILES: FC1C=CC(N2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]([CH2:22][CH2:23][CH3:24])[C:19]([OH:21])=O)=[CH:14][CH:15]=3)C=N2)=CC=1.[F:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]2C3C(=CC(C(C4C=CC=CC=4)C(C)(C)CN)=CC=3)[CH:40]=[N:39]2)=[CH:34][CH:33]=1.FC1C=CC([N:66]2C3C(=CC(C(C4C=CC=CC=4)C(CCC)C(F)=O)=CC=3)C=N2)=CC=1.N>C1COCC1.O>[F:31][C:32]1[CH:33]=[CH:34][C:35]([N:38]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]([CH2:22][CH2:23][CH3:24])[C:19]([NH2:66])=[O:21])=[CH:14][CH:15]=3)[CH:40]=[N:39]2)=[CH:36][CH:37]=1
Reactant: CC(C)(CN)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reactant: CCCC(C(=O)F)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reactant: CCCC(C(=O)O)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: N
Solvent: C1CCOC1
Solvent: O
Product: CCCC(C(N)=O)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
(c)(d) 2-((1-(4-fluorophenyl)-1H-indazol-5-yl)(phenyl)methyl)pentanoic acid (50, mg, 0.124 mmol) was converted into the acid fluoride using the identical procedure to that for Synthetic Intermediate I above. A solution of 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-propyl-3-phenylpropanoyl fluoride (0.32 mmol) in anhydrous THF (5 mL) at −78° C. was bubbled NH3 (g) for 10 minutes. The reaction mixture was sealed and stirred at −78° C. for 15 min and at rt for 1 hr. Water (100 mL) was added, the reaction mixture was extracted with ethyl acetate (100 mL), dried (Na2SO4), and concentrated to give 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-propyl-3-phenylpropanamide.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]#[CH:15])[CH:5]=[CH:4][C:3]1=2.Br[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[CH3:1][C:2]1([CH3:16])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: N#Cc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC1(C)CCC(C)(C)c2cc(C#Cc3ccc(C#N)cc3)ccc21

Procedure:
A mixture of 4 g (19 millimoles) of (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphth-2-yl)-ethyne, 2.8 g (12.5 millimoles) of 4-bromobenzonitrile, 50 mg of palladium (II) acetate, 100 mg of triphenylphosphine and 25 ml of degased anhydrous triethylamine was refluxed for 4 hours under nitrogen. Thereafter, solid material was filtered off and the filtrate was evaporated down.
Reaction SMILES: [NH2:1][C:2]([CH3:10])([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([OH:5])=[O:4].C([O-])([O-])=O.[K+].[K+].[O:17](C(OC(C)(C)C)=O)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=O>O1CCCC1.O>[C:21]([O:20][C:18]([NH:1][C:2]([CH3:10])([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([OH:5])=[O:4])=[O:17])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CC(C)CC(C)(N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CC(C)(NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a stirred solution of 2-amino-2,4-dimethylpentanoic acid (1 g, 6.89 mmol) in tetrahydrofuran (15 mL) and water (15 mL) was added K2CO3 (3.81 g, 27.5 mmol) and the reaction mixture was stirred at room temperature for 10 min. To the resultant mixture (BOC)2O (3.20 mL, 13.77 mmol) was added dropwise and the reaction mixture was allowed to stir at room temperature for 14 h. The reaction mixture was then concentrated under reduced pressure. The aqueous layer was washed with ethyl acetate (3×15 mL) and acidified with a saturated aqueous solution of citric acid (25 mL) then extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with water (2×15 mL), brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure to afford 2-((tert-butoxycarbonyl)amino)-2,4-dimethylpentanoic acid (1.6 g, 6.89 mmol, quantitative yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 5.36 (bs, 1 H), 2.10 (m, 1 H), 1.77 (m, 2 H), 1.74-1.65 (m, 3 H), 1.59 (s, 9 H), 0.89 (m, 3 H), 0.94 (m, 3 H).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14](=[NH:16])[NH2:15])=[CH:8][CH:7]=1)(=[O:4])=[O:3].[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(OCC)C>N1C=CC=CC=1>[CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[C:17]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14](=[NH:16])[NH2:15])=[CH:8][CH:7]=1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CS(=O)(=O)Oc1ccc(C=CC(=N)N)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CS(=O)(=O)O
Product: N=C(N)C=Cc1ccc(OC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 500 mg of 4-(β-amidinoethenyl)phenol methanesulfonate in 5 ml of pyridine, while being cooled in ice, was added 300 mg of benzoyl chloride. The resulting solution was stirred overnight at room temperature, then admixed with ethyl ether, again stirred thoroughly, and the ether layer was removed by decantation. This treatment was repeated once more and the residual solid substance was recrystallized from a methanol-ethyl ether mixture to obtain 4-(β-amidinoethenyl)-phenyl benzoate methanesulfonate.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:11]([N:13]1[CH2:17][C@@H:16]([CH3:18])[CH2:15][C@H:14]1[C:19]1[NH:20][C:21]([C:24]2[CH:29]=[C:28]3[CH2:30][O:31][C:32]4[CH:59]=[C:58]5[C:35]([CH:36]=[CH:37][C:38]6[N:42]=[C:41]([C@@H:43]7[CH2:47][C@H:46]([CH2:48][O:49][CH3:50])[CH2:45][N:44]7C(OC(C)(C)C)=O)[NH:40][C:39]=65)=[CH:34][C:33]=4[C:27]3=[CH:26][CH:25]=2)=[CH:22][N:23]=1)=[O:12])[C@@H:7]([CH2:9][CH3:10])[CH3:8])=[O:4].[CH3:60][O:61][C:62]([NH:64][C@@H:65]([C@@H:69]([CH3:72])[CH2:70][CH3:71])[C:66](O)=[O:67])=[O:63].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>Cl.CCO.CN(C=O)C>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([C@H:7]([CH3:8])[CH2:9][CH3:10])[C:11]([N:13]1[CH2:17][C@@H:16]([CH3:18])[CH2:15][C@H:14]1[C:19]1[NH:20][C:21]([C:24]2[CH:29]=[C:28]3[CH2:30][O:31][C:32]4[CH:59]=[C:58]5[C:35]([CH:36]=[CH:37][C:38]6[N:42]=[C:41]([C@@H:43]7[CH2:47][C@H:46]([CH2:48][O:49][CH3:50])[CH2:45][N:44]7[C:66](=[O:67])[CH:65]([NH:64][C:62](=[O:63])[O:61][CH3:60])[C@H:69]([CH3:72])[CH2:70][CH3:71])[NH:40][C:39]=65)=[CH:34][C:33]=4[C:27]3=[CH:26][CH:25]=2)=[CH:22][N:23]=1)=[O:12])=[O:4]
Reactant: CC[C@@H](C)[C@H](NC(=O)OC)C(=O)N1C[C@@H](C)C[C@H]1c1ncc(-c2ccc3c(c2)COc2cc4c(ccc5nc([C@@H]6C[C@H](COC)CN6C(=O)OC(C)(C)C)[nH]c54)cc2-3)[nH]1
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCO
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC[C@@H](C)C(NC(=O)OC)C(=O)N1C[C@@H](COC)C[C@H]1c1nc2ccc3cc4c(cc3c2[nH]1)OCc1cc(-c2cnc([C@@H]3C[C@H](C)CN3C(=O)[C@@H](NC(=O)OC)[C@H](C)CC)[nH]2)ccc1-4
Reaction time: 3 h
Yield: 86 %

Procedure:
tert-butyl (2S,4S)-2-[9-(2-{(2S,4S)-1-[N-(methoxycarbonyl)-L-alloisoleucyl]-4-methylpyrrolidin-2-yl}-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate (105 mg, 0.13 mmol) in 1.25 N HCl in EtOH (3 mL) was heated to 50° C. for 3 h and then concentrated under reduced pressure. The crude residue was treated with (2S,35)-2-(methoxycarbonylamino)-3-methylpentanoic acid (34 mg, 0.18 mmol), HATU (59 mg, 0.16 mmol) and DMF (1.3 mL), then N-methylmorpholine (0.043 mL, 0.39 mmol) was added dropwise. After 3 h, the mixture was quenched with 1N HCl (0.100 mL) and then purified by HPLC to afford methyl {(3R)-1-[(2S,4S)-2-(9-{2-[(2S,4S)-1-{(2S,3R)-2-[(methoxycarbonyl)amino]-3-methylpentanoyl}-4-methylpyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl}carbamate (98 mg, 86%).
Reaction SMILES: [SH:1][CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].CC(C)=O.Br[CH2:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22]>O>[Cl:20][C:18]1[CH:17]=[CH:16][C:15]([N+:21]([O-:23])=[O:22])=[C:14]([CH:19]=1)[CH2:13][S:1][CH2:2][C:3]([OH:5])=[O:4]
Reactant: O=C(O)CS
Reactant: O=[N+]([O-])c1ccc(Cl)cc1CBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)CSCc1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 20 h
Yield: 69.7 %

Procedure:
Mercapto-acetic acid (1.39 ml, 20 mmol) was dissolved in a 3.3 molar aqueous solution of sodium hydroxide (12 ml, 40 mmol) and cooled in an ice bath, before an acetone (50 ml) solution of 2-Bromomethyl-4-chloro-1-nitro-benzene (T. J. McCord et al, J. Het. Chem. 1972, 119–122)(5 g, 20 mmol) was added slowly. The resulting solution was stirred for 20 hours at room temperature before being diluted with water (50 ml) and extracted with dichloromethane (25 ml). The aqueous phase was made acidic with acetic acid and extracted with dichloromethane (2×25 ml). The combined organics were washed with brine, dried (MgSO4), filtered and evaporated to give the title product as an off-white foam (3.65 g).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[H-].[Na+].[CH2:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>C1COCC1.O>[CH2:13]([O:20][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)c1cccnc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccnc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.1 %

Procedure:
2-Chloro-nicotinic acid (421) (3 g, 19.04 mmol) was dissolved in anhydrous THF (50 mL) and chilled to 0° C. on an ice bath. NaH (50 mmol, 60% suspension in mineral oil) was added portion wise to the solution over a period of 5 minutes. The resulting mixture was stirred at 0° C. for 30 minutes. Benzyl-alcohol (422) (2.27 g, 21 mmol) was added drop wise over a period of 10 minutes. The ice bath was removed and the mixture was warmed to room temperature over a period of 2 h. The mixture was refluxed for 16 h. LC-MS and TLC (Rf: 0.4–0.5 compared to Rf: 0.1 for compound 421 in 1:1 hexane/EtOAc, single spot) indicated complete reaction at this point. The mixture was diluted with water (300 mL) and the pH was adjusted to ˜6 by the addition of HCl (aqueous, 1M) and the product was extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (100 mL) via extraction, dried over MgSO4 and concentrated under reduced pressure to give a yellow oil. Recrystallization from EtOAc/hexane gave the desired product (423) as a white powder (2.8 g, 12.2 mmol, 64% yield). LC-MS (ESI): (exact mass: 229.07) m/e=230.2 [M+1]+ (100%), 459.3 [2M+1]+ (90%).
Reaction SMILES: C(OC([N:8]1[CH:12]=[CH:11][C:10]([N:13]([C:17]([C:19]2[C:24]([N:25]([S:29]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([C:39]([F:42])([F:41])[F:40])[CH:33]=3)(=[O:31])=[O:30])COC)=[CH:23][C:22]([Cl:43])=[CH:21][N:20]=2)=[O:18])[CH:14]([CH3:16])[CH3:15])=[N:9]1)=O)(C)(C)C>Cl.O1CCOCC1.O>[CH:14]([N:13]([C:10]1[CH:11]=[CH:12][NH:8][N:9]=1)[C:17]([C:19]1[C:24]([NH:25][S:29]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([C:39]([F:42])([F:41])[F:40])[CH:33]=2)(=[O:30])=[O:31])=[CH:23][C:22]([Cl:43])=[CH:21][N:20]=1)=[O:18])([CH3:16])[CH3:15]
Reactant: COCN(c1cc(Cl)cnc1C(=O)N(c1ccn(C(=O)OC(C)(C)C)n1)C(C)C)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CC(C)N(C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)c1cc[nH]n1
Temperature: 85 °C

Procedure:
3-({5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carbonyl}-isopropyl-amino)-pyrazole-1-carboxylic acid tert-butyl ester from step 2 was dissolved in a mixture of 4 M HCl in dioxane (4 mL) and water (1 mL), heated to 85° C. for 2 h. The solvent was evaporated and the residue was purified with HPLC to give 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid isopropyl-(1H-pyrazol-3-yl)-amide. MS m/z: 522 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([N:13]([O:15][CH3:16])[CH3:14])=[O:12])=[C:7]2[N+:17]([O-])=O.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:17][C:7]1[C:6]2[C:10](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=2)[NH:9][C:8]=1[C:11]([N:13]([O:15][CH3:16])[CH3:14])=[O:12]
Reactant: CON(C)C(=O)c1[nH]c2c(Cl)cccc2c1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CON(C)C(=O)c1[nH]c2c(Cl)cccc2c1N
Temperature: 50 °C
Yield: 75.4 %

Procedure:
To a solution of 7-chloro-2-[(N-methoxy-N-methylamino)carbonyl]-3-nitroindole (step 2, 420 mg, 1.5 mmol) in ethanol-water (2:1, 30 ml) was added iron powder (168 mg, 3 mmol) and ammonium chloride (160 mg, 3 mmol). The mixture was heated at 50° C. for 2 h, and then cooled to room temperature. After filtration through a pad of Celite, the filtrate was concentrated. The residue was purified by flash column chromatography eluting with ethyl acetate/hexane (1:10˜1:1) to give 287 mg (75%) of the title compound.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1([CH2:15][C:16](=[O:20])[C:17](O)=[O:18])[CH2:14][CH2:13]1.[NH2:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[C:27](=[O:28])[O:26][CH2:25]2>>[F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1([CH2:15][C:16](=[O:20])[C:17]([NH:21][C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[C:27](=[O:28])[O:26][CH2:25]3)=[O:18])[CH2:13][CH2:14]1
Reactant: Nc1ccc2c(c1)COC2=O
Reactant: O=C(O)C(=O)CC1(c2cccc(C(F)(F)F)c2F)CC1
Product: O=C(CC1(c2cccc(C(F)(F)F)c2F)CC1)C(=O)Nc1ccc2c(c1)COC2=O

Procedure:
Preparation from 3-[1-(2-fluoro-3-trifluoromethylphenyl)-cyclopropyl]-2-oxo-propionic acid and 5-aminophthalide analogously to the preparation of 5-{3-[1-(2-fluoro-5-trifluoromethylphenyl)-cyclopropyl]-2-oxo-propionylamino}-phthalide (cf. Example 1a)). M.p. 157-158° C.
Reaction SMILES: [CH3:1][N:2]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[H-].[Na+].[CH2:13](Br)[C:14]#C.[Cl-].[Na+].[CH3:19]N(C)C=O>>[CH2:1]([N:2]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][C:4]([O:6][CH3:19])=[O:5])[C:13]#[CH:14]
Reactant: C#CCBr
Reactant: COC(=O)N(C)CC(=O)O
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Product: C#CCN(CC(=O)OC)C(=O)OC
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
5.0 g of methyl N-methoxycarbonylglycine were dissolved in 30 ml of N,N-dimethylformamide. Then ice-cooling the mixture, 1.5 g of sodium hydride (60% oil dispersion) were added thereto under a nitrogen atmosphere and stirred for 20 minutes. Thereafter 6.0 g of propargyl bromide were dropped thereto over 15 minutes and further stirred for 40 minutes. Then the reaction mixture was poured into ice-water and sodium chloride was added thereto to saturate the same. Then the aqueous layer was washed with hexane and it was subjected to two times of extraction with 100 ml of ether. The ether layers were combined together and dried over anhydrous magnesium sulfate and the solvent was evaporated off to obtain 3.9 g of methyl N-propargyl-N-methoxycarbonylglycinate (nD18 : 1.4891).