Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:27]COC)=[C:7]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[C:12]=3[N:13]=2)[CH:8]=1.BrCC1C2N=[C:40](C3C=C(OC)C(OC)=CC=3OCOC)[O:41]C=2C=CC=1>>[CH3:40][O:41][C:4]1[C:3]([O:2][CH3:1])=[CH:8][C:7]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[C:12]=3[N:13]=2)=[C:6]([OH:27])[CH:5]=1
Reactant: COCOc1cc(OC)c(OC)cc1-c1nc2c(CBr)cccc2o1
Reactant: COCOc1ccc(OC)cc1-c1nc2c(CNCc3ccccn3)cccc2o1
Product: COc1cc(O)c(-c2nc3c(CNCc4ccccn4)cccc3o2)cc1OC

Procedure:
2-(4,5-dimethoxy-2-hydroxyphenyl)-4-(2-pyridylmethyl)aminomethyl-benzoxazole (F19) was prepared in a similar manner for the preparation of 2-(5-methoxy-2-methoxymethoxyphenyl)-4-(2-pyridylmethyl)aminomethylbenzoxazole (F16) using 4-bromomethyl-2-(4,5-dimethoxy-2-methoxymethoxyphenyl)benzoxazole (F13) (612 mg, 1.59 mmol) instead of 4-bromomethyl-2-(5-methoxy-2-methoxymethoxyphenyl)benzoxazole (F12) in 17% (112 mg); 1H-NMR (500 MHz, CDCl3) δ3.56 (s, 3H), 3.95 (s, 3H), 3.97 (s, 3H), 4.02 (s, 2H), 4.30 (s, 2H), 5.27 (s, 2H), 6.85 (s, 1H), 7.15 (dd, 1H, J=7.5, 5.0 Hz), 7.28 (t, 1H, J=7.5 Hz), 7.33 (d, 1H, J=7.5 Hz), 7.42 (d, 1H, J=7.5 Hz), 7.47 (d, 1H, J=7.5 Hz), 7.64 (m, 2H), 8.55 (d, 1H, J=5.0 Hz).
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=O)(=O)[CH3:2].[C:11]([CH2:13][C:14]([NH2:16])=[O:15])#[N:12].N1CCCCC1>C(O)C>[C:11]([C:13]1[C:14](=[O:15])[NH:16][C:1]([CH3:2])=[C:4]2[C:9]=1[CH2:8][CH2:7][CH2:6][CH2:5]2)#[N:12]
Reactant: CC(=O)C1CCCCC1=O
Reactant: N#CCC(N)=O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(=O)c(C#N)c2c1CCCC2
Yield: 67 %

Procedure:
2-Acetylcyclohexanone (5 g) and cyanoacetamide (3 g) were added to 25 ml of ethanol and a small amount of piperidine was also added. The mixture was heated under reflux for 2 hours. After cooling, deposited crystals were filtered out and washed with ethanol. There was obtained 4.5 g of 4-cyano-2,3,5,6,7,8-hexahydro-1-methyl-3-oxoisoquinoline.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]([NH2:19])=[N:13][C:14]=2[C:15]([F:18])([F:17])[F:16])O1.B(O[O-])=[O:22].O.[Na+].CCOC(C)=O>C1COCC1.O>[NH2:19][C:12]1[N:13]=[C:14]([C:15]([F:18])([F:17])[F:16])[C:9]([OH:22])=[CH:10][CH:11]=1
Reactant: O=BO[O-]
Reactant: CC1(C)OB(c2ccc(N)nc2C(F)(F)F)OC1(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ccc(O)c(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.9 %

Procedure:
A solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)pyridin-2-amine (0.598 g, 2.076 mmol) in THF (10 mL) and water (10 mL) was treated with sodium perborate monohydrate (0.332 g, 3.32 mmol) and stirred at RT overnight. The mixture was treated with EtOAc and the solids removed via filtration through diatomaceous earth. The filtrate was treated with brine, extracted with EtOAc (3×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford 6-amino-2-(trifluoromethyl)pyridin-3-ol (92 mg, 25%). 1H NMR (400 MHz, DMSO-d6): δ 9.47 (s, 1H), 7.15 (d, J=8.9 Hz, 1H), 6.58 (d, J=8.9 Hz, 1H), 5.70 (s, 2H); MS (ESI) m/z: 179.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:11]=[C:12]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([OH:23])=[CH:18][C:17]=3[CH3:24])[CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:4][C:3]=1[CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].[CH3:32][C:33]1[N:38]=[C:37]([CH2:39]O)[CH:36]=[CH:35][CH:34]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH3:22][C:21]1[CH:20]=[C:19]([O:23][CH2:39][C:37]2[CH:36]=[CH:35][CH:34]=[C:33]([CH3:32])[N:38]=2)[CH:18]=[C:17]([CH3:24])[C:16]=1[C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][O:8][C:6]2[CH:5]=[CH:4][C:3]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:2]([F:1])[CH:7]=2)[CH:11]=1
Reactant: CCOC(=O)CCc1ccc(OCc2cccc(-c3c(C)cc(O)cc3C)c2)cc1F
Reactant: Cc1cccc(CO)n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccc(OCc2cccc(-c3c(C)cc(OCc4cccc(C)n4)cc3C)c2)cc1F
Yield: 86.8 %

Procedure:
To a solution of ethyl 3-{2-fluoro-4-[(4′-hydroxy-2′,6′-dimethylbiphenyl-3-yl)methoxy]phenyl}propanoate (1.2 g, 2.84 mmol), (6-methylpyridin-2-yl)methanol (0.39 g, 3.12 mmol) and triphenylphosphine (0.95 g, 3.61 mmol) in tetrahydrofuran (24 mL) was added diisopropyl azodicarboxylate (40% toluene solution, 1.54 mL, 3.12 mmol) at room temperature with stirring. The reaction mixture was stirred at room temperature for 12 hrs., and an equivalent amount of the aforementioned reagents ((6-methylpyridin-2-yl)methanol, triphenylphosphine and diisopropyl azodicarboxylate) were added. The mixture was further stirred at the same temperature for 12 hrs. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=1/1) to give the title compound (1.3 g, yield 87%) as a colorless oil.
Reaction SMILES: [OH-].[Na+].O.[CH3:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]1[CH2:14][C:15]3[C:20]([C:8]2=1)=[CH:19][CH:18]=[CH:17][CH:16]=3.[CH3:21]I>C1C=CC=CC=1>[CH3:21][N:10]1[C:11]2[C:7](=[CH:6][C:5]([CH3:4])=[CH:13][CH:12]=2)[C:8]2[C:20]3[C:15]([CH2:14][C:9]1=2)=[CH:16][CH:17]=[CH:18][CH:19]=3
Reactant: CI
Reactant: Cc1ccc2[nH]c3c(c2c1)-c1ccccc1C3
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2C)Cc2ccccc2-1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
45 g of NaOH, 60 ml of water, 60 ml of benzene, 0.3 g of trimethyl-cethyl-ammonium bromide, 19.3(0.088 mol) of 2-methyl-5,6-dihydroindeno[2,1-b]indole, prepared in Example 8-bis, and 7.5 ml (0.12 mol) of CH3I were placed in a bulb. The resulting two-phase system was stirred for 2 hours at room temperature and then 10 minutes at reflux. Then the reaction mixture cooled to room temperature and filtered. The obtained precipitate was washed twice with ethanol and finally dried, thus obtaining 18 g of N-methyl-2-methyl-5,6-dihydroindeno[2,1-b]indole (yield=88%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1>C1(C)C=CC=CC=1>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[NH:10][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: Nc1ccccn1
Solvent: Cc1ccccc1
Product: Oc1ccc(CNc2ccccn2)cc1
Yield: 56.2 %

Procedure:
4-Hydroxybenzaldehyde (3.9 g, 32 mmol) and 2-aminopyridine (3.0 g, 32 mmol) were stirred in toluene (100 ml) at room temperature for 5 min. After concentrating in vacuo the residue was dissolved in ethanol (50 ml) and hydrogenated over Pd/C (100 mg) under a hydrogen atmosphere, for 18 h. The reaction mixture was filtered, concentrated and the crude product was chromatographed (dichloromethane-silica) to yield the title compound as white crystals (3.6 g, 56%). 1H NMR (CDCl3) δ 8.10 (1H, m), 7.49 (1H, m), 7.14 (2H, d, J 7.8 Hz), 6.79 (2H, d, J 7.8 Hz), 6.64 (1H, m), 6.47 (1 H, d, J 7.8 Hz), 4.79 (1H, br s) and 4.32 (2H, d, J 5.2 Hz).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1.C(N(CC)CC)C.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[C:41]([OH:48])(=[O:47])/[CH:42]=[CH:43]/[C:44]([OH:46])=[O:45]>C(Cl)(Cl)Cl>[C:41]([OH:48])(=[O:47])/[CH:42]=[CH:43]/[C:44]([OH:46])=[O:45].[C:32]([NH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: NCCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C(O)/C=C/C(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(NCCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1)c1ccccc1
Reaction time: 1.5 h

Procedure:
To a solution of 1-(3-aminopropyl)-4-(4-chlorobenzhydryl)piperazine (1.7 g) and triethylamine (0.7 g) in chloroform (20 ml) was dropwise added benzoyl chloride (0.7 ml) at ambient temperature and the mixture was stirred at the same temperature for 1.5 hours. The reaction mixture was washed successively with aqueous sodium bicarbonate and water, and then extracted with 10% hydrochloric acid. After neutralizing the aqueous extract with aqueous sodium carbonate, the desired product was extracted with ethyl acetate. The organic extract was washed with water, dried and evaporated in vacuo to give an oil. According to a conventional manner, the oily product was converted to fumaric acid salt, which was recrystallized from a mixture of ethanol and diethyl ether to afford 1-(3-benzoylaminopropyl)-4-(4-chlorobenzhydryl)piperazine fumarate (0.82 g) as white crystals. mp: 173°-175° C. (dec.).
Reaction SMILES: [CH3:1]N(C=O)C.[Br:6][C:7]1[CH:8]=[C:9]([NH:13][C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][CH:12]=1.[H-].[Na+].CI>O>[Br:6][C:7]1[CH:8]=[C:9]([N:13]([CH3:1])[C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][CH:12]=1
Reactant: CN(C)C=O
Reactant: CC(=O)Nc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CC(=O)N(C)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94 %

Procedure:
To a DMF solution (15 ml) of N-(3-bromo-phenyl)-acetamide (1.19 g) obtained in Step A, 60% oily sodium hydride (279 mg) was added, followed by stirring at room temperature for 10 minutes. To this, methyl iodide (434 μl) was added, followed by stirring at room temperature for 21 hours. To this, water (30 ml) was added, followed by extraction with ethyl acetate (30 ml×2), and the organic layer was dried over sodium sulfate. The sodium sulfate was filtered off, followed by purification by silica gel column chromatography (dichloromethane/methanol=200/1), to obtain the desired compound (1.20 g, 94%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([SH:11])[NH:9][CH:10]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:18]([C:20]1[CH:29]=[CH:28][C:23]([C:24](=[O:27])[CH2:25]Br)=[CH:22][C:21]=1[F:30])#[N:19]>C(#N)C>[C:18]([C:20]1[CH:29]=[CH:28][C:23]([C:24](=[O:27])[CH2:25][S:11][C:8]2[NH:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:10][N:9]=2)=[CH:22][C:21]=1[F:30])#[N:19]
Reactant: N#Cc1ccc(C(=O)CBr)cc1F
Reactant: CCOC(=O)c1c[nH]c(S)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cnc(SCC(=O)c2ccc(C#N)c(F)c2)[nH]1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
To a solution 4-ethoxycarbonylimidazole-2-thiol (8.47 g, 49.2 mmol) and potassium carbonate (20.4 g, 148 mmol) in dry acetonitrile (200 mL) at room temperature was added bromide from Step G (11.9 g, 49.2 mmol). The reaction mixture was stirred for 20 hours, during which time a white precipitate formed. To the solution was added 100 mL ice water. The resulting solid was filtered and washed with water (2×25 mL) to provide the title product as an off-white solid which was sufficiently pure for use in the next step.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([F:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[CH3:25][O:26][C:27](=[O:32])[CH2:28][C:29](Cl)=[O:30]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([N:16]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[C:29](=[O:30])[CH2:28][C:27]([O:26][CH3:25])=[O:32])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([F:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(F)ccc2n1NCc1ccc(F)cc1
Reactant: COC(=O)CC(=O)Cl
Product: CCOC(=O)c1cc2cc(F)ccc2n1N(Cc1ccc(F)cc1)C(=O)CC(=O)OC

Procedure:
Prepared according to the acylation condition used in Example 2 step f) from 5-fluoro-1-(4-fluoro-benzylamino)-1H-indole-2-carboxylic acid ethyl ester and chlorocarbonyl-acetic acid methyl ester (1.2 eq.). 1H NMR (CDCl3, δ in ppm): 7.3-6.77 (m, 8H), 4.82 (dd, 2H), 4.17 (m, 2H), 3.54 (s, 3H), 3.26 (s, 2H), 1.31 (t, 3H, J=7.1 Hz).
Reaction SMILES: CCN(C(C)C)C(C)C.O.NN.[NH2:13][C:14]1[C:15]2[C:22]([C:23]#[C:24][C:25]3[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[C:27]([O:33][CH3:34])[CH:26]=3)=[CH:21][N:20]([C@@H:35]3[CH2:39][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C@H:37]([C:47](O)=[O:48])[CH2:36]3)[C:16]=2[N:17]=[CH:18][N:19]=1.CN(C(O[N:58]1[N:66]=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.O.C(OCC)(=O)C>[NH2:13][C:14]1[C:15]2[C:22]([C:23]#[C:24][C:25]3[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[C:27]([O:33][CH3:34])[CH:26]=3)=[CH:21][N:20]([C@@H:35]3[CH2:39][N:38]([C:40]([O:42][C:43]([CH3:44])([CH3:46])[CH3:45])=[O:41])[C@H:37]([C:47]([NH:58][NH2:66])=[O:48])[CH2:36]3)[C:16]=2[N:17]=[CH:18][N:19]=1
Reactant: COc1cc(C#Cc2cn([C@H]3C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C3)c3ncnc(N)c23)cc(OC)c1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: NN
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C#Cc2cn([C@H]3C[C@@H](C(=O)NN)N(C(=O)OC(C)(C)C)C3)c3ncnc(N)c23)cc(OC)c1

Procedure:
DIPEA (73 μl) and hydrazine monohydrate (46 μl) were added to a solution of (2S,4S)-4-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (106 mg) obtained in Step 1 above and TBTU (100 mg) in DMF (2 ml), and the resulting mixture was stirred at room temperature for 10 minutes. Ethyl acetate and water were added to the reaction mixture to separate the organic layer, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound as a light-yellow, amorphous substance (93.6 mg). Physical properties: m/z [M+H]+ 522.4
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:20]([NH:22][C@H:23]([C:39]([NH:41][C@H:42]([C:52]([NH:54][C@@H:55]([C:57]([OH:59])=[O:58])[CH3:56])=[O:53])[CH2:43][O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:40])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:27][CH:26]=1)=[O:21])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:60]O>C(N(CC)CC)C>[CH3:60][O:58][C:57](=[O:59])[C@@H:55]([CH3:56])[NH:54][C:52](=[O:53])[C@H:42]([CH2:43][O:44][CH2:45][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)[NH:41][C:39](=[O:40])[C@H:23]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[CH:27][CH:26]=1)[NH:22][C:20](=[O:21])[C@H:9]([CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: CO
Reactant: C[C@@H](NC(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(=O)O
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](C)NC(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C
Reaction time: 48 h

Procedure:
Nα-t-Butoxycarbonyl-L-tryptophyl-O-benzyl-L-tyrosyl-O-benzyl-L-seryl-D-alanine resin, 7.1 g., prepared in Example 1 is mixed with methanol, 600 ml., and triethylamine, 60 ml., at room temperature for 2 days. After filtration and evaporation, the crude product, 2.7 g., is chromatographed on silica gel with chloroform-methanol-water (60:30:5) to yield 1.9 g., m.p. 178°-182° C.
Reaction SMILES: [O:1]=[C:2]([N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[C:3](=[O:5])[CH3:4].S(Cl)([Cl:15])(=O)=O>C(Cl)(Cl)Cl>[Cl:15][CH2:4][C:3](=[O:5])[C:2]([N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:1]
Reactant: CC(=O)C(=O)N1CCCCC1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=C(CCl)C(=O)N1CCCCC1
Reaction time: 0.21 h

Procedure:
To a hot (50°) solution of the product of step B in 20 ml chloroform, 2.61 g (1.55 ml) of sulfuryl chloride is added dropwise (using a syringe) with vigorous stirring over a period of from 10 to 15 minutes. The mixture is stirred for about 7 hours at 50°. The mixture is then quenched by pouring into water. The resulting mixture is then extracted with methylene chloride. The combined extracts are washed with 10% aq. sodium bicarbonate solution then brine, dried over anh. sodium sulfate, then concentrated (under vacuum) to obtain an oily residue. The oil is distilled under vacuum (0.01 mm Hg) at 100° (constant boiling point) to obtain an oil which is re-distilled (at 0.001 mm Hg) at 90° C. for 1/2 hr. to obtain refined title product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=[CH:9][S:8][C:7]=1[NH2:19])=[O:5])[CH3:2].[C:20]1(=O)[O:25][C:23](=[O:24])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=[CH:9][S:8][C:7]=1[N:19]1[C:23](=[O:24])[C:22]2[C:21](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20]1=[O:25])=[O:5])[CH3:2]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCOC(=O)c1c(-c2cccc(OC)c2)csc1N
Solvent: CC(=O)O
Product: CCOC(=O)c1c(-c2cccc(OC)c2)csc1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
A mixture of 2-amino-4-(3-methoxyphenyl)-thiophene-3-carboxylic acid ethyl ester (2 mmol, Example 18 & 19, Part B) and phthalic anhydride (2.2 mmol) in glacial acetic acid (20 mL) is heated at reflux overnight. After cooling to room temperature, the acetic acid is removed in vacuo and the residue triturated with petroleum ether. The crude product is collected by filtration, suspended in acetyl chloride (5 mL), and heated to reflux for one hour. After removing the solvent in vacuo, the residue is dissolved in ethyl acetate (30 mL), washed sequentially with 5% aqueous NaHCO3 (10 mL), water (10 mL), brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo. Recrystallization affords the desired product.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:23]([O-:25])=[O:24])=[C:6]([N:8]2[C:13](=[O:14])[N:12]([CH3:15])[C:11](=[O:16])[N:10]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:9]2=[O:22])[CH:7]=1.[OH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(Cl)Cl.CO>[CH3:15][N:12]1[C:13](=[O:14])[N:8]([C:6]2[CH:7]=[C:2]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[CH:3]=[CH:4][C:5]=2[N+:23]([O-:25])=[O:24])[C:9](=[O:22])[N:10]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:11]1=[O:16]
Reactant: COC(=O)Cn1c(=O)n(C)c(=O)n(-c2cc(F)ccc2[N+](=O)[O-])c1=O
Reactant: Oc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)Cn1c(=O)n(C)c(=O)n(-c2cc(Oc3ccccn3)ccc2[N+](=O)[O-])c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 3-(5-fluoro-2-nitrophenyl)tetrahydro-5-methyl-2,4,6-trioxo-s-triazine-1(2H)-acetate (0.55 g, 1.55 mmol), 2-hydroxypyridine (0.25 g, 2.58 mmol) and potassium carbonate (0.37 g, 2.64 mmol) in N,N-dimethylformamide is stirred at room temperature overnight and poured into water. The aqueous mixture is extracted with ethyl acetate. The organic extracts are combined, washed sequentially, with water, 0.2M sodium hydroxide solution, water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a yellow foam. Column chromatography of the foam using silica gel and a 2% methanol in methylene chloride solution gives the title product as a yellow oil which is identified by NMR spectral analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([S:15][CH3:16])=[CH:12][CH:13]=2)[C:8]([OH:17])=[N:7]1.[H-].[Na+].[OH:24][C:25]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][C:26]=1[CH2:27]Cl.O>CS(C)=O>[OH2:17].[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([S:15][CH3:16])=[CH:12][CH:13]=2)[C:8](=[O:17])[N:7]1[CH2:27][C:26]1[CH:29]=[C:30]([N+:33]([O-:35])=[O:34])[CH:31]=[CH:32][C:25]=1[OH:24]
Reactant: O=[N+]([O-])c1ccc(O)c(CCl)c1
Reactant: CSc1ccc2c(c1)c(O)nn2Cc1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CSc1ccc2c(c1)c(=O)n(Cc1cc([N+](=O)[O-])ccc1O)n2Cc1ccc(Cl)c(Cl)c1
Reaction time: 2 h

Procedure:
3.6 g (11 mmol) of 1-(3,4-dichlorobenzyl)-5-methylthio-1H-indazol-3-ol are dissolved in 100 ml of DMSO and treated in portions with 0.34 g (13.2 mmol) of sodium hydride (95 percent). After stirring for 2 hours, a solution of 2.1 g (11 mmol) of 2-hydroxy-5-nitrobenzyl chloride in 20 ml of DMSO is added dropwise and the mixture is stirred at 60° C. for 3 hours. After cooling, 200 ml of water are added dropwise, the mixture is stirred for 4 hours and the solid is filtered off with suction. The precipitate is extracted by stirring with methanol whilst hot and recrystallized from 2-propanol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([CH:12]([CH3:14])[CH3:13])[C@:7]([CH2:16][CH2:17][N:18]([CH2:20][CH2:21][CH2:22][NH:23][CH2:24][C:25]([CH2:30][O:31][CH3:32])([CH3:29])[CH2:26][O:27][CH3:28])[CH3:19])([OH:15])[CH2:6][CH2:5]2.CCN(C(C)C)C(C)C.[F:42][CH2:43][C:44](Cl)=[O:45]>C(Cl)Cl>[F:42][CH2:43][C:44]([N:23]([CH2:22][CH2:21][CH2:20][N:18]([CH2:17][CH2:16][C@@:7]1([OH:15])[CH2:6][CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[C@@H:8]1[CH:12]([CH3:14])[CH3:13])[CH3:19])[CH2:24][C:25]([CH2:26][O:27][CH3:28])([CH3:29])[CH2:30][O:31][CH3:32])=[O:45]
Reactant: COCC(C)(CNCCCN(C)CC[C@@]1(O)CCc2cc(F)ccc2[C@@H]1C(C)C)COC
Reactant: O=C(Cl)CF
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCC(C)(COC)CN(CCCN(C)CC[C@@]1(O)CCc2cc(F)ccc2[C@@H]1C(C)C)C(=O)CF
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2.73 g of (1S,2S)-6-fluoro-1-isopropyl-2-(2-{[3-(3-methoxy-2-methoxymethyl-2-methyl-propylamino)-propyl]-methyl-amino}-ethyl)-1,2,3,4-tetrahydro-naphthalen-2-ol in DCM (29 mL) was added at 0° C., 1.5 mL of DIPEA and 1.1 mL of fluoroacetyl chloride. The mixture was stirred for 20 min at 0° C. then allowed to warm up to rt for 1 h and quenched with sat.-NaHCO3. The organic phase was dried over anh. Na2SO4 and concentrated in vacuo. The resulting crude ester was dissolved in EtOH (29 mL) and treated with 15 mL of a 1M NaOH solution. The mixture was stirred for 15 min at rt and concentrated in vacuo. The resulting residue was taken up in DCM and washed with sat.-NaHCO3 and brine. The organic phase was dried over anh. Na2SO4 and concentrated in vacuo. The resulting crude was purified by CC using EtOAc/MeOH/NEt3 from 100/0/1 to 90/10/1 to yield 2.07 g of 2-fluoro-N-(3-{[2-((1S,2S)-6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydro-naphthalen-2-yl)-ethyl]-methyl-amino}-propyl)-N-(3-methoxy-2-methoxymethyl-2-methyl-propyl)-acetamide as orange oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:21](OC)=[O:22])=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][CH:14]=1)[CH:8]=[CH:7][CH:6]=2.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C(OCC)C>[Br:1][C:2]1[C:3]([CH2:21][OH:22])=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH3:20])=[CH:17][CH:18]=1)[CH:8]=[CH:7][CH:6]=2
Reactant: CCc1ccc(Cc2cccc3cc(C(=O)OC)c(Br)cc23)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CCc1ccc(Cc2cccc3cc(CO)c(Br)cc23)cc1
Yield: 98.9 %

Procedure:
Under a nitrogen stream, methyl 3-bromo-5-[(4-ethylphenyl)methyl]-2-naphthoate (334.1 mg, 0.87 mmol) was dissolved in diethyl ether (10.0 mL). To the resultant mixture was added lithium aluminum hydride (39.7 mg, 1.04 mmol) under ice-cooling, and the resultant mixture was stirred for 30 minutes. Water was added thereto, and the resultant mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, to thereby obtain the titled compound (305.8 mg, 89%).