Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:4]=[N:5][NH:6][CH:7]=1.[H-].[Na+].F[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]2[CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[S:23][CH:24]=2)[N:14]=1.O>CC(N(C)C)=O>[F:1][C:2]([F:9])([F:8])[C:3]1[CH:4]=[N:5][N:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]3[CH:21]=[C:22]([C:25]([F:26])([F:27])[F:28])[S:23][CH:24]=3)[N:14]=2)[CH:7]=1
Reactant: FC(F)(F)c1cn[nH]c1
Reactant: Fc1cccc(Oc2csc(C(F)(F)F)c2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: FC(F)(F)c1cnn(-c2cccc(Oc3csc(C(F)(F)F)c3)n2)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 14.9 %

Procedure:
0.114 g of 4-trifluoromethylpyrazole is introduced in 5 ml of dimethylacetamide under nitrogen and at 0° C. 0.028 g of NaH is added. The mixture is allowed to come to RT over 30 min and then 0.2 g of 2-fluoro-6-(2-trifluormethyl-4-thienyloxy)pyridine is added and the mixture is heated at 80° C. for 9 h, cooled to RT and poured into water. After threefold extraction with ethyl acetate the product is washed with water and saturated sodium chloride solution, dried over MgSO4 and concentrated. Chromatographic purification on silica gel with heptane/ethyl acetate (3:7) as eluent gives 0.043 g of 2-(4-trifluoromethylpyrazol-1-yl)-6-(2-trifluoromethyl-4-thienyloxy)pyridine as colorless crystals.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]4[OH:32])=[CH:21][C:20]=3[OH:33])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:34](Cl)(=[O:46])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45].N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:13]1([C:11]2[N:12]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]4[O:32][C:34](=[O:46])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[CH:21][C:20]=3[OH:33])[N:10]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: Oc1cc(OC2CCCCC2O)ccc1-c1nc(-c2ccccc2)nc(-c2ccccc2)n1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCC(=O)OC1CCCCC1Oc1ccc(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)c(O)c1
Reaction time: 20 h

Procedure:
A mixture of 5.0 g (11.3 mmol) of 2,4-diphenyl-6-(2'-hydroxy-4'-(2"- hydroxycyclohexyloxy)phenyl)-1,3,5-triazine, 5.7 g (26 mmol) of dodecanoyl chloride (Fluka, 98%) and 0.1 g (1.3 mmol) of pyridine in 60 ml of toluene is stirred under nitrogen and kept at 50° C. for 20 h.
Reaction SMILES: N12CCCN=C1CCCCC2.[F:12][C:13]([F:27])([F:26])[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]2[NH:21][O:22][C:23](=[O:25])[N:24]=2)[CH:15]=1.[CH3:28][O:29][N:30]([CH3:34])[C:31](Cl)=[O:32]>N1C=CC=CC=1>[F:27][C:13]([F:12])([F:26])[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]2[N:24]([C:31]([N:30]([O:29][CH3:28])[CH3:34])=[O:32])[C:23](=[O:25])[O:22][N:21]=2)[CH:15]=1
Reactant: CON(C)C(=O)Cl
Reactant: O=c1nc(-c2cc(C(F)(F)F)ccn2)[nH]o1
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: CON(C)C(=O)n1c(-c2cc(C(F)(F)F)ccn2)noc1=O
Temperature: 50 °C
Reaction time: 4 h
Yield: 69 %

Procedure:
To 1 ml of pyridine were added 0.18 g of 1,8-diazabicyclo[5,4,0]undec-7-ene, and 0.2 g of 3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-one, and 0.15 g of N-methoxy-N-methylcarbamoyl chloride was added at room temperature. After stirring at 50° C. for 4 hours, the resultant solution was concentrated, and the residue was subjected to silica gel column chromatography to obtain 0.19 g of 3-(4-trifluoromethylpyridin-2-yl)-N-methoxy-N-methyl-1,2,4-oxadiazol-5-one-4-carboxamide (present compound (21))
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[OH-].[K+].[CH:12]1([SH:17])[CH2:16][CH2:15][CH2:14][CH2:13]1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:17][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][N:3]=1
Reactant: SC1CCCC1
Reactant: ClCc1ccc(Cl)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Clc1ccc(CSC2CCCC2)cn1
Reaction time: 16 h
Yield: 82 %

Procedure:
Slurry 2-chloro-5-chloromethyl-pyridine (8.1 g, 45 mmol) and potassium hydroxide (10.3 g, 225 mmol) in methanol at 0° C. under nitrogen atmosphere. Add cyclopentyl mercaptan (4.8 mL, 45 mmol), warm the mixture to room temperature and stir for 16 h. Concentrate in vacuo and partition the residue between water (50 mL) and DCM (200 mL). Collect the organic phase, concentrate in vacuo and purify the crude mixture by chromatography on silica gel (330 g) eluting with hexane/EtOAc (49:1 to 4:1 gradient) to obtain the desired intermediate as an oil (8.4 g, 82%). MS (APCI+) m/z: 227 (M)+.
Reaction SMILES: [I-].BrC1C=CC=C[N+]=1C.[C:10]([OH:14])([CH3:13])([CH3:12])[CH3:11].[C:15]1([CH2:21][C:22](O)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[C:15]1([CH2:21][C:22]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: CC(C)(C)O
Agent: C[n+]1ccccc1Br
Agent: [I-]
Solvent: CCCCN(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Cc1ccccc1
Yield: 82 %

Procedure:
To a suspended toluene (2 ml) solution of 2-bromo-1-methylpyridinium iodide (720 mg, 2.4 mmol) was added a mixture of tert-butyl alcohol (148 mg, 2.0 mmol), phenylacetic acid (272 mg, 2.0 mmol) and tri-n-butylamine (888 mg, 4.8 mmol) in toluene (2 ml), and the resulting mixture was refluxed for 3 hours. After evaporation of the solvent, the residue was separated by silica gel column chromatography, and tert-butyl phenylacetate was isolated in 82% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[C:11]([Cl:15])=[CH:10][C:3]=1[O:4][CH2:5][C:6]([NH:8][NH2:9])=[O:7].[C:16]([C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)(=O)[CH3:17].O1CCOCC1>C(O)(=O)C>[N:22]1[CH:23]=[CH:24][C:19]([C:16](=[N:9][NH:8][C:6](=[O:7])[CH2:5][O:4][C:3]2[CH:10]=[C:11]([Cl:15])[C:12]([Cl:14])=[CH:13][C:2]=2[Cl:1])[CH3:17])=[CH:20][CH:21]=1
Reactant: NNC(=O)COc1cc(Cl)c(Cl)cc1Cl
Reactant: CC(=O)c1ccncc1
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CC(=NNC(=O)COc1cc(Cl)c(Cl)cc1Cl)c1ccncc1
Temperature: 25 °C
Yield: 83.7 %

Procedure:
A solution of 5.39 gm (0.02 mole) of 2,4,5-trichlorophenoxyacetic acid hydrazide, 2.42 gm (0.02 mole) of 4-acetylpyridine, 125 ml of dioxane and 2 ml of acetic acid is refluxed 4 hr. The hot solution is filtered. The filtrate is diluted with water until cloud point. The mixture is cooled to room temperature and then chilled in the refrigerator. The product is collected to yield 6.24 gm (83%) of the title compound having a melting point of 227.4° C. (decomp).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][NH:15][CH:16]2[C:19]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[CH2:21][CH2:20]2)=[CH:11][C:10]=1[O:29][CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:37][O:38][CH2:39][CH2:40]Br>CC(C)=O>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][N:15]([CH2:40][CH2:39][O:38][CH3:37])[CH:16]2[C:19]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[CH2:20][CH2:21]2)=[CH:11][C:10]=1[O:29][CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(cc1OCc1ccccc1)C(C1(c3ccccc3Cl)CC1)NCC2
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCCN1CCc2cc(OC)c(OCc3ccccc3)cc2C1C1(c2ccccc2Cl)CC1
Reaction time: 16 h

Procedure:
A mixture of 7-benzyloxy-1-[1-(2-chlorophenyl)cyclopropyl]-6-methoxy-1,2,3,4-tetrahydroisoquinoline (2.1 g, free base liberated from the hydrobromide salt prepared in a similar manner to that described in Example RC14), acetone (30 ml), anhydrous potassium carbonate (1.6 g) and 2-methoxyethyl bromide (2.1 g) was heated under reflux for 6 hours. After a further 16 hours at ambient temperature, potassium carbonate (3 g) and 2-methoxyethyl bromide (2.22 g) were added, and heating continued for 6 hours. The mixture was filtered, the residue washed with acetone, and solvent removed from the filtrate in vacuo to yield 7-benzyloxy-1-[1-(2-chlorophenyl)cyclopropyl]-6-methoxy-2-(2-methoxyethyl)-1,2,3,4-tetrahydroisoquinoline as an oil.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[C:4]([Br:13])[N:3]=1.[CH3:14][O-:15].[Na+].O>CO>[Br:13][C:4]1[C:5]([N+:10]([O-:12])=[O:11])=[CH:6][C:7]([O:8][CH3:9])=[C:2]([O:15][CH3:14])[N:3]=1
Reactant: C[O-]
Reactant: COc1cc([N+](=O)[O-])c(Br)nc1Br
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc([N+](=O)[O-])c(Br)nc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
20 g of 2,6-dibromo-3-methoxy-5-nitropyridine (example E3) were dissolved in 550 ml of anhydrous methanol at 30-40° C. 4.6 g sodium methoxide dissolved in 30 ml anhydrous methanol were added to this solution. The reaction mixture was stirred for one hour at room temperature, poured into 700 ml of water and stored in the refrigerator overnight. The precipitate was filtered, washed with ice cold water and dried under vacuum to yield the title compound.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[C:15]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25])[C:14]([CH3:26])=[C:13]([CH3:27])[N:12]=1>O1CCOCC1>[CH3:27][C:13]1[C:14]([CH3:26])=[C:15]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25])[C:16]([N+:17]([O-:19])=[O:18])=[C:11]([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:12]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(NCCCCO)c1C
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCCCCO)c1C
Reaction time: 8 h
Yield: 43.6 %

Procedure:
Sodium hydride (4.38 g of 60% dispersion in mineral oil, 109.6 mmol) was added to chilled dioxane (73 mL). Phenol (10.31 g, 109.6 mmol) was added in portions with cooling. 4-[(2-Chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]butan-1-ol (20.00 g, 93.07 mmol) and additional dioxane (˜30 mL) were added. The reaction mixture was heated at reflux for 3 hours and then allowed to stand at ambient temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (200 mL) and then extracted with ethyl acetate (300 mL). The extract was washed with water (2×100 mL) then with brine, dried over magnesium sulfate, filtered and then concentrated under reduced pressure to provide an oil. The oil was purified by flash chromatography (600 mL of silica gel, eluting initially with 2000 mL 1:3 ethyl acetate:hexanes, then with 2000 mL 1:1 ethyl acetate:hexanes and finally with 1000 mL 3:1 ethyl acetate:hexanes) to provide 13.46 g of 4-[(2,3-dimethyl-5-nitro-6-phenoxypyridin-4-yl)amino]butan-1-ol as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]1([OH:18])[CH2:16][C@H:15]([CH3:17])[CH2:14][C@@H:13]2[C@H:9]1[CH2:10][NH:11][CH2:12]2.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C@H:27]([CH3:31])[C:28](O)=[O:29]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]1([OH:18])[CH2:16][C@H:15]([CH3:17])[CH2:14][C@@H:13]2[C@H:9]1[CH2:10][N:11]([C:28](=[O:29])[C@H:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[O:20][CH3:19])[CH3:31])[CH2:12]2
Reactant: C[C@@H]1C[C@H]2CNC[C@H]2[C@](O)(c2ccccc2F)C1
Reactant: COc1ccccc1[C@H](C)C(=O)O
Product: COc1ccccc1[C@H](C)C(=O)N1C[C@@H]2C[C@@H](C)C[C@@](O)(c3ccccc3F)[C@@H]2C1
Yield: 48.5 %

Procedure:
By working as in Example 33, but starting with 2.5 g of (3aS,4S,6R,7aR)-4-(2-fluorophenyl)-6-methyl-4-perhydroisoindolol and 2.17 g of 2-(S)-(2-methoxyphenyl)propionic acid, and after purification on a column of silica gel (particle size 0.04-0.06 mm, diameter 4 cm, height 25 cm), eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (90/10 by volume), 3.87 g of a solid are obtained, which solid is recrystallized in acetonitrile to give 2 g of (3aS,4S,6R,7aR)-4-(2-fluorophenyl)-2-[2-(S)-(2-methoxyphenyl) propionyl]-6- methyl-4-perhydroisoindolol, in the form of a white solid melting at 170° C.
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:7][C@H:6](O)[CH2:5][C@@H:4]1[C:9]([OH:11])=[O:10])[CH3:2].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.CCOCC>C(Cl)Cl.C([C@@H]1C[C@H]2C[C@@H]1C(=O)O2)C>[CH2:1]([CH:3]1[CH2:7][CH:6]2[CH2:5][CH:4]1[C:9](=[O:10])[O:11]2)[CH3:2]
Reactant: CC[C@@H]1C[C@H](O)C[C@@H]1C(=O)O
Agent: CC[C@@H]1C[C@H]2C[C@@H]1C(=O)O2
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCOCC
Solvent: ClCCl
Product: CCC1CC2CC1C(=O)O2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a scalemic mixture enriched in (1S,2R,4S)-2-ethyl-4-hydroxycyclopentanecarboxylic acid (0.943 g, 5.96 mmol) in DCM (60 mL) was added TEA (2.5 mL, 18 mmol) and BOP-Cl (1.821 g, 7.15 mmol). The reaction mixture was stirred at ambient temperature for about 2 h then poured into Et2O (350 mL). The solid was removed by filtration while washing with Et2O (50 mL). The filtrate was concd under reduced pressure to give a yellow oil which was dissolved in DCM (5 mL) and Et2O was added to give a solid. The supernatant was decanted and the solid was washed with additional Et2O. The combined organic extracts were concd under reduced pressure to give a scalemic mixture enriched in crude (1S,4S,5R)-5-ethyl-2-oxabicyclo[2.2.1]heptan-3-one containing about 15 mol % TEA (0.912 g, 99%): 1H NMR (CDCl3) δ 4.85 (s, 1H), 2.88 (s, 1H), 2.19 (m, 2H), 2.08 (m, 1H), 1.69 (m, 1H), 1.41 (m, 3H), 0.97 (t, J=5.4, 3H).
Reaction SMILES: C([O:8][C:9]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][N:18]=2)[CH:13]=[CH:12][C:10]=1[NH2:11])C1C=CC=CC=1>O1CCCC1.CO.[Pd]>[NH2:11][C:10]1[CH:12]=[CH:13][C:14]([O:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][N:18]=2)=[CH:15][C:9]=1[OH:8]
Reactant: CS(=O)(=O)c1ccc(Oc2ccc(N)c(OCc3ccccc3)c2)nc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CS(=O)(=O)c1ccc(Oc2ccc(N)c(O)c2)nc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 77.3 %

Procedure:
To a solution of 2-(benzyloxy)-4-{[5-(methylsulfonyl)pyridin-2-yl]oxy}aniline (46 g) in a mixture of tetrahydrofuran (400 mL) and methanol (150 mL) was added palladium on carbon (7 g, 10 weight %, wet), and the mixture was stirred at room temperature for 15 h under hydrogen atmosphere. The mixture was filtered to remove the catalyst and the filtrate was concentrated. The residual solid was washed with methanol-diethyl ether to give the title compound (26.91 g, 84%) as a greenish-gray solid. MS 281 (MH+).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([C:10]2[NH:14][CH:13]=[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:11]=2[F:25])=[CH:8][CH:7]=[CH:6][N:5]=1.C1OCCOCCOCCOCCOC1.Cl[S:42]([C:45]1[CH:49]=[CH:48][S:47][C:46]=1[C:50]([O:52][CH3:53])=[O:51])(=[O:44])=[O:43]>O1CCCC1>[C:19]([O:18][C:17]([N:16]([CH2:15][C:12]1[C:11]([F:25])=[C:10]([C:9]2[C:4]([F:3])=[N:5][CH:6]=[CH:7][CH:8]=2)[N:14]([S:42]([C:45]2[CH:49]=[CH:48][S:47][C:46]=2[C:50]([O:52][CH3:53])=[O:51])(=[O:43])=[O:44])[CH:13]=1)[CH3:24])=[O:23])([CH3:21])([CH3:22])[CH3:20]
Reactant: COC(=O)c1sccc1S(=O)(=O)Cl
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1sccc1S(=O)(=O)n1cc(CN(C)C(=O)OC(C)(C)C)c(F)c1-c1cccnc1F
Reaction time: 0.08 h
Yield: 97 %

Procedure:
To a suspension of sodium hydride (60% in oil, 14.8 mg) in tetrahydrofuran (3 mL) was added tert-butyl {[5-(2-fluoropyridin-3-yl)-4-fluoro-1H-pyrrol-3-yl]methyl}methylcarbamate (100 mg) under ice-cooling, and the mixture was stirred for 5 min. 15-Crown-5 (81.7 mg) and methyl 3-(chlorosulfonyl)thiophene-2-carboxylate were added dropwise and the mixture was further stirred under ice-cooling for 2 hr. The reaction mixture was concentrated under reduced pressure, diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→2:1) to give the title compound as a pale-yellow oil (yield 158 mg, 97%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[CH:27]=[C:26]([F:28])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[OH:29])=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].[CH:30]1(O)[CH2:33][CH2:32][CH2:31]1>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[CH:27]=[C:26]([F:28])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[O:29][CH:30]2[CH2:33][CH2:32][CH2:31]2)=[O:17])[CH2:7][C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(NC(=O)c2cc(F)c3ccccc3c2O)Cc2ccccc2C1
Reactant: OC1CCC1
Solvent: ClCCl
Product: CCOC(=O)C1(NC(=O)c2cc(F)c3ccccc3c2OC2CCC2)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 144 h

Procedure:
A solution of 2-[(4-fluoro-1-hydroxynaphthalene-2-carbonyl)amino]indan-2-carboxylic acid ethyl ester (303) (197 mg, 0.5 mmol) and 3,3-dimethyl-1,2,5-thiadiazolidine-5 triphenylphosphine-1,1-dioxide (example 307, 245 mg, 0.6 mmol, 1.2 eq) in DCM (6 mL) is treated with cyclobutanol (44 mg, 0.6 mmol, 1.2 eq) and stirred at RT for 6 days. The crude reaction mixture is purified by flash chromatography (100 g silica gel, 100% DCM) to give colorless oil. (120 mg, 54%)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[Br:8][C:9]1[CH:14]=[C:13](Br)[CH:12]=[C:11]([Br:16])[CH:10]=1>>[Br:8][C:9]1[CH:14]=[C:13]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:12]=[C:11]([Br:16])[CH:10]=1
Reactant: Nc1cccnc1
Reactant: Brc1cc(Br)cc(Br)c1
Product: Brc1cc(Br)cc(Nc2cccnc2)c1

Procedure:
3-Aminopyridine was coupled with 1,3,5-tribromobenzene to give (3,5-dibromo-phenyl)-pyridin-3-yl-amine by the method described in Example 44. The reaction was complete in 1 hour. The dibromide was converted to N-[3-bromo-5-(pyridin-3-ylamino)-phenyl]-acetamide by the method of Example 82.
Reaction SMILES: C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:42][C@@H:43]([CH2:62][C:63]1[N:64]=[CH:65][NH:66][CH:67]=1)[C:44]([NH:46][C@@H:47]([CH2:55][CH:56]1[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]1)[C@@H:48]([OH:54])[C@H:49]([CH:51]1[CH2:53][CH2:52]1)[OH:50])=[O:45].[CH:68]1([CH2:71][O:72][C:73]([C:75]([S:78]([CH2:81][CH:82]([CH2:86][C:87]2[CH:92]=[CH:91][CH:90]=[CH:89][CH:88]=2)[C:83](O)=[O:84])(=[O:80])=[O:79])([CH3:77])[CH3:76])=[O:74])[CH2:70][CH2:69]1>CN(C)C=O>[CH:56]1([CH2:55][C@H:47]([NH:46][C:44]([C@@H:43]([NH:42][C:83]([C@@H:82]([CH2:86][C:87]2[CH:88]=[CH:89][CH:90]=[CH:91][CH:92]=2)[CH2:81][S:78]([C:75]([CH3:76])([CH3:77])[C:73]([O:72][CH2:71][CH:68]2[CH2:70][CH2:69]2)=[O:74])(=[O:80])=[O:79])=[O:84])[CH2:62][C:63]2[N:64]=[CH:65][NH:66][CH:67]=2)=[O:45])[C@@H:48]([OH:54])[C@H:49]([CH:51]2[CH2:52][CH2:53]2)[OH:50])[CH2:57][CH2:58][CH2:59][CH2:60][CH2:61]1
Reactant: CC(C)(C(=O)OCC1CC1)S(=O)(=O)CC(Cc1ccccc1)C(=O)O
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C(=O)OCC1CC1)S(=O)(=O)C[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.3 %

Procedure:
77 mg (0.76mmol) of triethylamine, 118 mg (0.76mmol) of HOBT and 289 mg (0.76 mmol) of HBTU were added in sequence at room temperature under nitrogen to a solution of 250 mg (0.69mmol) of (S)-α-amino-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]imidazole-4propionamide and 281 mg (0.76 mmol) of rac-α-[[[1-[(cyclopropylmethoxy)carbonyl]-1-methylethyl]sulfonyl]methyl]hydrocinnamic acid in 20 ml of dimethylformamide. The yellow reaction solution was stirred at room temperature overnight. For the working-up, the reaction solution was evaporated in a high vacuum. The residue was taken up in 40 ml of ethyl acetate and extracted twice with in each case 10 ml of saturated sodium hydrogen carbonate solution and 10 ml of saturated sodium chloride solution. The organic extracts were dried over sodium sulphate and subsequently evaporated under reduced pressure. For purification, the residue (560 mg) was chromatographed on 50 g of silica gel using a 95:5:0.1 mixture of methylene chloride, methanol and pyridine as the eluent. After lyophilization from dioxan/water there were obtained 110 mg of the less polar cyclopropylmethyl 2-[[(R)-2-[[(S)-1-[[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]-3-phenylpropyl]sulfonyl]-2-methylpropionate, MS: 715 (M+H)+, and 142 mg of the more polar epimeric cyclopropylmethyl 2-[[(S)-2-[[(S)-1-[[(1S,2R,3S)-1 -(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]-3-phenylpropyl]sulfonyl]-2-methylpropionate, MS: 715 (M+H)+, each as a colourless powder.
Reaction SMILES: [CH3:1][P:2]([O-:8])[O:3][CH2:4][CH:5]([CH3:7])[CH3:6].[CH3:9][C:10]([O:12][CH:13]([C:16]#[N:17])[CH:14]=[CH2:15])=[O:11]>>[C:10]([O:12][CH:13]([C:16]#[N:17])[CH2:14][CH2:15][P:2]([CH3:1])(=[O:8])[O:3][CH2:4][CH:5]([CH3:7])[CH3:6])(=[O:11])[CH3:9]
Reactant: C=CC(C#N)OC(C)=O
Reactant: CC(C)COP(C)[O-]
Product: CC(=O)OC(C#N)CCP(C)(=O)OCC(C)C
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 100.9 %

Procedure:
208 g of isobutyl methanephosphonite are heated to 80° C. under nitrogen. 0.5 g of tert.-butyl perpivalate is added to the hot reaction solution, and 63.9 g of acrolein cyanohydrin acetate and 2.5 g of tert.-butyl perpivalate are added dropwise within 2.3 hours. The mixture is stirred at 80° C. for 5 min, and 133.9 g of isobutyl methanephosphonite are distilled out under high vacuum (recovery: 91.3%; purity: 97%). 134.6 g of isobutyl (3-acetoxy-3-cyanopropyl)methylphosphinate (yield: 97.8%, purity 95%) are obtained.
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2>O.C(O)(=O)C>[CH3:20][O:19][C:11]1[C:12]([O:17][CH3:18])=[CH:13][C:14]2[C:15]3[CH:16]=[N:1][NH:5][C:6]=3[CH:7]=[N:8][C:9]=2[CH:10]=1
Reactant: COc1cc2ncc(N)c(C)c2cc1OC
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc2ncc3[nH]ncc3c2cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.4 %

Procedure:
Sodium nitrite (1.28 g, 18.60 mmol), dissolved in water (2.5 ml), is added to a solution of 3-amino-6,7-dimethoxy-4-methylquinoline (2.70 g, 12.39 mmol) in glacial acetic acid (90 ml). The reaction mixture is stirred at room temperature for 3 h. When the reaction is complete, the mixture is evaporated in vacuo. The residue is taken up in water, filtered and rinsed with water. The filtrate is evaporated to dryness in vacuo. The residue obtained is filtered off with suction a number of times through a little flash silica gel in a frit with cyclohexane/ethyl acetate 4:1 (parts by volume) in order to remove impurities. The filtrate is discarded. The filter cake is subsequently washed with ethyl acetate/0-10% by vol. of ethanol, and the filtrate is evaporated to dryness in vacuo, giving 7,8-dimethoxy-3H-pyrazolo[3,4-c]-quinoline (2.29 g, purity 85%, 8.48 mmol) as a solid. MS: 230.0 (M+H+), TLC (HPTLC): Rf=0.45 (ethyl acetate/ethanol 8:1, parts by volume).