Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:18])(=O)=O>C(NCC(C)C)C(C)C.C1(C)C=CC=CC=1>[Cl:18][C:10]1[CH:9]=[C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:13]=[CH:12][C:11]=1[OH:14]
Reactant: O=S(=O)(Cl)Cl
Reactant: Oc1ccc(Oc2ccccc2)cc1
Agent: CC(C)CNCC(C)C
Solvent: Cc1ccccc1
Product: Oc1ccc(Oc2ccccc2)cc1Cl
Temperature: 70 °C
Yield: 121.2 %

Procedure:
To a 54 ml toluene solution of 4-phenoxyphenol (2 g, 10.7 mmol) and diisobutylamine (0.15 ml, 0.86 mmol) was added sulfuryl chloride (0.69 ml, 8.6 mmol). The mixture was heated to 70° C. for 3 hr. The solvent was removed under reduced pressure. The residue was diluted with AcOEt and aq sat. bicarbonate solution. The organic layer was separated, and the aqueous layer was extracted twice with AcOEt. The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and chromatographed on silica gel. Elution with 15% AcOEt/hexanes gave the title compound 2.3 g as colorless syrup (97%).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH:15]1([CH2:18][C:19]#[N:20])[CH2:17][CH2:16]1>C1COCC1>[C:19]([C:18]([CH:15]1[CH2:17][CH2:16]1)=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1)#[N:20]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: N#CCC1CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=C(C#N)C2CC2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl 4-oxopiperidine-1-carboxylate (2.0 g, 10 mmol) and cyclopropylacetonitrile (0.97 g, 12 mmol) were dissolved in THF (20 mL), heated to reflux, and allowed to stir for 3 hours. The mixture was then cooled to ambient temperature and concentrated in vacuo. The residue was purified by MPLC on silica gel to afford the title compound as a white solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[C:7]([O:14][CH3:15])[CH:6]=1)(=[O:4])=[O:3]>CO.ClCCl.[Pd]>[CH3:1][S:2]([C:5]1[CH:10]=[C:9]([CH:8]=[C:7]([O:14][CH3:15])[CH:6]=1)[NH2:11])(=[O:3])=[O:4]
Reactant: COc1cc([N+](=O)[O-])cc(S(C)(=O)=O)c1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(N)cc(S(C)(=O)=O)c1

Procedure:
1-Methylsulfonyl-3-methoxy-5-nitro-benzene (1.3 g; 5.6 mmol) was dissolved in methanol (40 ml) and 80 mg Pd/C (5% w/w) were added and the reaction mixture was hydrogenated at 2 bar. The mixture was then diluted with dichloromethane, filtrated above over a celite pad, concentrated and the residual was crystallized from methanol. 0.5 g (2.48 mmol; 44% yield) of a solid were obtained.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[BH4-].[Na+]>C(O)C>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)N1CCC(O)CC1
Reaction time: 48 h

Procedure:
A solution of 1-isopropyl-piperidin-4-one (51.2 g) in absolute ethanol (350 mL) was treated with sodium borohydride (7.30 g) at a rate not to exceed an internal temperature of 50° C. After 48 h, the solvent was evaporated and the resulting yellow paste was partitioned between DCM (300 mL) and 5% NaOH (300 mL). This mixture was stirred for 6 h and then extracted with DCM (4×100 mL). The combined organic phases were dried (sodium sulfate) and evaporated. Distillation of the yellow oil (bp 68° C., 1.5 mm Hg) gave the title compound as an off-white waxy solid (35.3 g).
Reaction SMILES: [Br:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[O:13][CH3:14].C([N:17](CC)CC)C.ClC(OCC)=O.N>C(OCC)(=O)C.C1COCC1>[Br:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6]([NH2:17])=[O:7])=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: COc1cc(C(=O)O)cc(OC)c1Br
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: N
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(C(N)=O)cc(OC)c1Br
Yield: 78.8 %

Procedure:
To a mixture of 4-bromo-3,5-dimethoxybenzoic acid (15 g, 57.6 mmol) and THF (200 mL) were added triethylamine (9.63 mL, 69.0 mmol) and ethyl chloroformate (5.79 mL, 60.6 mmol) while stirring on ice, and the resulting mixture was stirred for 20 minutes while cooling on ice. After adding 28% aqueous ammonia to the mixture and stirring at room temperature for 2 hours, ethyl acetate was further added. After then thoroughly shaking the mixture, the organic layer was separated and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The mixture was filtered, and the solvent in the filtrate was distilled off under reduced pressure. The obtained residue (solid) was washed with diethyl ether and collected by filtration to obtain the title compound (11.8 g, 45.4 mmol).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH:6]([C:9]2[NH:10][C:11]([C:15]3[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=3[CH3:25])[C:18]([O:20]C)=[O:19])=[C:12]([CH3:14])[N:13]=2)[CH2:5][CH2:4]1.[OH-].[Na+]>CO.O>[CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH:6]([C:9]2[NH:10][C:11]([C:15]3[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=3[CH3:25])[C:18]([OH:20])=[O:19])=[C:12]([CH3:14])[N:13]=2)[CH2:5][CH2:4]1
Reactant: COC(=O)c1ccc(C)c(-c2[nH]c(C3CCC(OC)CC3)nc2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC1CCC(c2nc(C)c(-c3cc(C(=O)O)ccc3C)[nH]2)CC1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-(2-(4-methoxycyclohexyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoate (compound 300.2, 150 mg, 0.44 mmol) in methanol (4 mL). A solution of NaOH (70 mg, 1.75 mmol) in water (2 mL) was added to the reaction. The reaction mixture was stirred for 3 h at 50° C., then concentrated under reduced pressure. The reaction mixture was diluted with 2 mL of water. The pH of the solution was adjusted to 1 with HCl (2 M) and concentrated under reduced pressure. This resulted in 240 mg (crude) of the title compound as a light yellow solid.
Reaction SMILES: [F:1][C:2]([F:8])(F)[S:3]([O-:6])(=[O:5])=[O:4].[CH:9]1([S:15][C:16]2[CH:21]=[CH:20][C:19]([S+:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:18][CH:17]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[F:35][C:36]([F:42])(F)S([O-])(=O)=O.ClCl.[CH3:45]O>>[CH:29]12[CH2:45][CH:32]([CH2:31][CH2:30]1)[CH2:33][CH:34]2[C:36]([F:42])([F:35])[C:2]([F:8])([F:1])[S:3]([O-:6])(=[O:5])=[O:4].[CH:9]1([S:15][C:16]2[CH:21]=[CH:20][C:19]([S+:22]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:18][CH:17]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CO
Reactant: O=S(=O)([O-])C(F)(F)F
Agent: ClCl
Agent: c1ccc([S+](c2ccccc2)c2ccc(SC3CCCCC3)cc2)cc1
Product: O=S(=O)([O-])C(F)(F)C(F)(F)C1CC2CCC1C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
19.2 g of the resulting 4-cyclohexylthiophenyl diphenylsulfonium trifluoromethane sulfonate was dissolved in 100 g of methanol in a reaction flask. The mixture was fed into an ion-exchange chromatography (an ion-exchange resin: Shephadex R-QAE A-25, packing amount: 60 g, manufactured by Aldrich Corporation) to replace trifluoromethanesulfonate anions with chlorine ions. After evaporating methanol using an evaporator, the resulting residue was dissolved in 100 g of dichloromethane. 15 g of 30 wt % 2-(bicyclo[2.2.1]heptan-2-yl)-1,1,2,2-tetrafluoroethane sodium sulfonate aqueous solution was added. The mixture was stirred for one hour at room temperature and transferred to a separatory funnel, shaken, and allowed to stand still. The water layer was removed. 100 ml of distilled water was added and the mixture was shaken again and allowed to stand still. The water layer was removed. The resulting dichloromethane solution was dried with anhydrous magnesium sulfate and filtered. After evaporating dichloromethane from the dried solution, the residual liquid was dried under reduced pressure to obtain 20.1 g of 4-cyclohexylthiophenyl diphenylsulfonium 2-(bicyclo[2.2.1]heptan-2-yl)-1,1,2,2-tetrafluoroethanesulfonate.
Reaction SMILES: N[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][N:3]=1.N([O-])=O.[Na+].C([O-])([O-])=O.[Na+].[Na+].[H+].[B-](F)(F)(F)[F:27]>>[F:27][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][N:3]=1
Reactant: F[B-](F)(F)F
Reactant: CCn1c(=O)ccc2cnc(N)cc21
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Agent: [H+]
Product: CCn1c(=O)ccc2cnc(F)cc21
Yield: 64 %

Procedure:
A suspension of (XIII) (1.1 g, 5.8 mmol) in 48% aqueous HBF4 (20 mL) at -10° C. was treated with NaNO2 (0.44 g, 6.38 mmol, added in small portions over 3 hours). The resulting mixture was neutralized (pH 7) with solid Na2CO3 carefully, keeping the temperature below 0° C., and extracted with EtOAc (3×75 mL). The solvent was removed, then chromatography of the residue on silica gel, eluting with ethyl acetate, gave 7-fluoro-1-ethyl-1H-[1,6]naphthyridin-2-one (XV) (0.72 g, 64%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH3:17])=[CH:11][CH:10]=2)[C:5]([F:18])=[CH:4][N:3]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[NH2:24]>>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([NH:24][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH3:17])=[CH:11][CH:10]=3)[C:5]([F:18])=[CH:4][N:3]=2)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]
Reactant: CCOc1ccc(Nc2nc(Cl)ncc2F)cc1
Reactant: COc1ccc(N)cc1OC
Product: CCOc1ccc(Nc2nc(Nc3ccc(OC)c(OC)c3)ncc2F)cc1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-N4-(4-ethoxyphenyl)-5-fluoro-4-pyrimidineamine with 3,4-dimethoxyaniline gave N2-(3,4-dimethoxyphenyl)-N4-(4-ethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.89 (d, 1H, J=3 Hz), 7.45 (bd, 2H, J=9 Hz), 7.20 (d, 1H, J=2.4 Hz), 6.96-6.77 (m, 5H), 6.63 (bs, 1H), 4.03 (q, 2H, J=7.2 Hz), 3.86 (s, 3H), 3.72 (s, 3H), 1.42 (t, 3H, J=7.2 Hz); 19F NMR (CDCl3): −47473.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[C:5]2[C:6]([NH:8][C:9](=O)[C:4]=12)=O.B.CO.Cl>O1CCCC1>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[C:5]2[C:4]=1[CH2:9][NH:8][CH2:6]2
Reactant: COc1cccc2c1C(=O)NC2=O
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: COc1cccc2c1CNC2
Temperature: 0 °C
Yield: 58.9 %

Procedure:
A stirred solution of 3-methoxyphthalimide (8.95 g, 50.56 mmol) in anhydrous tetrahydrofuran (200 ml) at 0° C. was treated dropwise with a solution of borane in tetrahydrofuran (1M, 150 ml, 0.15 mol) and the resulting mixture was stirred and held at reflux for 16 hours. The mixture was cooled to 0° C., methanol (60 ml) was added dropwise followed by 5M hydrochloric acid (60 ml) and the mixture was stirred and held at reflux for 4 hours. Upon cooling to room temperature the organic solvent was removed in vacuo and the mixture diluted with water (250 ml) and extracted with dichloromethane (3×250 ml). The aqueous layer was basified to pH 12 or above by the addition of 5M sodium hydroxide, extracted with dichloromethane (3×250 ml) and the combined extracts were evaporated to dryness in vacuo to afford 4-methoxyisoindoline (4.44 g, 59%) as a green oil which was used without further purification. 1H NMR (DMSO-d6) 7.18 (1H, t), 6.83 (1H, d), 6.78 (1H, d), 4.07 (2H, s), 4.02 (2H, s), 3.78 (3H, s). MS: [M+H]+ 150.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:9]([NH:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:10].[CH:18]([C@@H:20]1[C@@H:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:23][N:22]([C@H:31]([CH:44]2[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]2)[C:32]([O:34]CC2C=CC(OC)=CC=2)=[O:33])[CH2:21]1)=O>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][C@@H:20]2[C@@H:24]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:23][N:22]([C@H:31]([CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]3)[C:32]([OH:34])=[O:33])[CH2:21]2)[CH2:14][CH2:13]1)=[O:10]
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Reactant: Cc1ccccc1OC(=O)NC1CCNCC1
Product: Cc1ccccc1OC(=O)NC1CCN(C[C@H]2CN([C@@H](C(=O)O)C3CCCCC3)C[C@@H]2c2ccccc2)CC1

Procedure:
The title compound was prepared from 4-((2-methylphenyl)oxycarbonylamino)-piperidine and 2-(R)-(3-(R)-formyl-4-(S)phenylpyrrolidin-1-yl)-2-(cyclohexyl)acetic acid, 4-methoxybenzyl ester (Aldehyde 5) according to the method described in Example 1, Step C. ESI-MS: 534 (M+H); HPLC A: 2.29 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[OH:12].[CH3:13][S:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](O)=[O:18].CCN=C=NCCCN(C)C.Cl>N1C=CC=CC=1>[OH:12][C:3]1[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=1[NH:1][C:17](=[O:18])[C:16]1[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=1[S:14][CH3:13]
Reactant: Nc1cc(C(F)(F)F)ccc1O
Reactant: CSc1ccccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Product: CSc1ccccc1C(=O)Nc1cc(C(F)(F)F)ccc1O
Temperature: 80 °C
Yield: 17.9 %

Procedure:
A mixture of 2-amino-4-trifluoromethylphenol (1.00 g), 2-methylsulfanylbenzoic acid (0.95 g), WSC (1.41 g), and pyridine (20 ml) was stirred with heating at 80° C. for 2.5 hours. Into the reaction mixture cooled to room temperature, 1 mol/l of hydrochloric acid was poured, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water, and saturated brine, sequentially, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 0.33 g of N-(2-hydroxy-5-trifluoromethylphenyl)-2-methylsulfanyl-benzamide (Compound (1B)-515).
Reaction SMILES: C1COC2(N)N(C(NC3C=CC4OC(CO)=CC=4C=3)=NC=C2F)O1.[Cl:25][C:26]1[N:31]=[C:30]([NH:32][C:33]2[CH:42]=[C:41]3[C:36]([CH2:37][CH2:38][CH2:39][C:40]3=[O:43])=[CH:35][CH:34]=2)[C:29]([F:44])=[CH:28][N:27]=1.CC(C[Al]CC(C)C)C>>[Cl:25][C:26]1[N:31]=[C:30]([NH:32][C:33]2[CH:42]=[C:41]3[C:36]([CH2:37][CH2:38][CH2:39][CH:40]3[OH:43])=[CH:35][CH:34]=2)[C:29]([F:44])=[CH:28][N:27]=1
Reactant: O=C1CCCc2ccc(Nc3nc(Cl)ncc3F)cc21
Agent: CC(C)C[Al]CC(C)C
Agent: NC12OCCON1C(Nc1ccc3oc(CO)cc3c1)=NC=C2F
Product: OC1CCCc2ccc(Nc3nc(Cl)ncc3F)cc21

Procedure:
In a manner similar to the preparation of N4-(3,4-ethylenedioxy)-5-fluoro-N2-[2-(hydroxymethyl)benzofuran-5-yl]-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-(1,2,3,4-tetrahydro-1-oxonaphthalen-7-yl)-4-pyrimidineamine was reduced with Dibal-H to yield 2-chloro-5-fluoro-N4-(1,2,3,4-tetrahydro-1-hydroxynaphthalen-7-yl)-4-pyrimidineamine. 1H NMR (CDCl3): δ 8.05 (d, 1H, J=3.0 Hz), 7.59 (d, 1H, J=2.4 Hz), 7.14 (d, 1H, J=8.1 Hz), 6.93 (bs, 1H), 4.82-4.78 (m, 1H), 2.82-2.71 (m, 2H), 2.08-1.74 (m, 5H); 19F NMR (282 MHz, CDCl3): −44661; LCMS: purity: 94%; MS (m/e): 294(MH+).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][N:10]=[CH:11][CH:12]([S:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[CH2:13][CH:14]([OH:16])[CH3:15].[CH3:24][S:25](Cl)(=[O:27])=[O:26].C(OCC)(=O)C>O1CCCC1.O>[CH3:24][S:25]([O:16][CH:14]([CH2:13][CH:12]([S:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[CH:11]=[N:10][O:9][CH3:8])[CH3:15])(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: CON=CC(CC(C)O)Sc1ccccn1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CON=CC(CC(C)OS(C)(=O)=O)Sc1ccccn1
Temperature: 15 °C
Reaction time: 1.5 h

Procedure:
1.2 mL of triethylamine was added to a solution of 1.7 g of 5-(methoxyimino)-4-(pyridin-2-ylsulfanyl)pentan-2-ol in 7.0 mL of tetrahydrofuran, and thereafter, 602 μL of methanesulfonyl chloride was added to the mixture at a temperature of 0° C. to 10° C. The thus obtained mixture was stirred at a temperature of 15° C. or lower for 1.5 hours. Thereafter, 50 mL of ethyl acetate and 50 mL of water were added to the reaction mixture, and the water layer was then removed. The organic layer was washed with a saturated sodium chloride aqueous solution, and was then dried over anhydrous magnesium sulfate. After that, the solvent was distilled away under reduced pressure, so as to obtain 2.12 g of 5-(methoxyimino)-4-(pyridin-2-ylsulfanyl)pentan-2-yl methanesulfonate in the form of a brown oily product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[F:10][C:11]([Si](C)(C)C)([F:13])[F:12].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]([OH:6])[C:11]([F:13])([F:12])[F:10])[CH:3]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1cccc(F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1cccc(F)c1)C(F)(F)F
Yield: 120.4 %

Procedure:
According to Reference Example 8-12, by use of 3-fluorobenzaldehyde (500 mg, 4.03 mmol), (trifluoromethyl)trimethylsilane (715 μL, 4.83 mmol), tetrabutylammonium fluoride (a 1.0 mol/L solution in tetrahydrofuran, 403 μL, 0.403 mmol) and tetrahydrofuran (10 mL), the mixture was stirred and reacted at room temperature for 3 hours. Thus, 1-fluoro-3-(2,2,2-trifluoro-1-hydroxyethyl)benzene (Compound DA) (942 mg, yield: quantitative) was obtained.
Reaction SMILES: CC(C[AlH]CC(C)C)C.[F:10][C:11]([F:29])([F:28])[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24](OC)=[O:25])[N:19]=2)=[CH:14][CH:13]=1>ClCCl>[F:29][C:11]([F:10])([F:28])[C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([CH:24]=[O:25])[N:19]=2)=[CH:16][CH:17]=1
Reactant: COC(=O)c1nccc(-c2ccc(C(F)(F)F)cc2)n1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: O=Cc1nccc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 25 °C
Yield: 21.4 %

Procedure:
DIBAL-H (2.3 mL, 2.300 mmol, 1.0 M in toluene) was slowly added to an orange solution of Example 33A (550 mg, 1.949 mmol) in dichloromethane (10 mL) at −75° C. The reaction was warmed to ambient temperature overnight. Quenched with methanol (10 mL), concentrated to an orange residue, and supported on silica gel. Chromatographed on a Grace Reveleris 12 g column, eluted with 0-60% EtOAc in dichloromethane (25 mL/min) to provide the title compound (135 mg, 0.418 mmol, 21.42% yield) as a beige solid, a mixture of 78% aldehyde and 22% methyl ester by proton NMR. MS (ESI+) m/z 253.1 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]([C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1)([CH3:14])([CH3:13])[CH3:12].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[C:11]([C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=1)[O:21][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC(C)(C)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)c1cccc(Oc2ccc([N+](=O)[O-])cn2)c1
Temperature: 25 °C
Reaction time: 70 h
Yield: 99.5 %

Procedure:
Following procedure A, 2-chloro-5-nitropyridine (300 mg, 1.89 mmol, 1.00 eq) and 3-tert-butylphenol (358 mg, 2.38 mmol, 1.26 eq) were dissolved in DMSO (6 mL). Anhydrous K2CO3 (420 mg, 3.04 mmol, 1.60 eq) was added and the reaction mixture was stirred at room temperature for 70 h. After extraction with Et2O, the crude product was purified by flash column chromatography (SiO2; EtOAc/petrolether 1:100) to afford the title compound as colourless solid (512 mg, 1.88 mmol, 99% yield). Rf=0.37 (EtOAc/PE 1:20). HRMS (ESI) calcd. for C15H17N2O3+ [M+H]+ 273.1234. found: 273.1232. 1H NMR (400 MHz, CDCl3) δ 9.08-9.04 (m, 2H, aromatic H), 8.47 (dd, J=9.1, 2.8 Hz, 1H, aromatic H), 7.39 (t, J=7.9 Hz, 1H, aromatic H), 7.33 (ddd, J=7.9, 1.8, 1.2 Hz, 1H, aromatic H), 7.17 (t, J=2.1 Hz, 1H, aromatic H), 7.01 (dd, J=9.1, 0.5 Hz, 1H, aromatic H), 6.98 (ddd, J=7.9, 2.4, 1.2 Hz, 1H, aromatic H), 1.34 (s, 9H, C(CH3)3). 13C NMR (101 MHz, CDCl3) δ 167.21, 153.88, 152.76, 145.26, 140.31, 134.93, 129.50, 123.17, 118.62, 118.47, 111.28, 35.02, 31.36.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:21])=[C:5]([O:11][C:12]2[CH:13]=[C:14]([CH:17]=[C:18]([Cl:20])[CH:19]=2)[C:15]#[N:16])[C:6]([CH2:9][CH3:10])=[CH:7][CH:8]=1.[Cl:22][C:23]1[N:24]=[CH:25][N:26]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:27]=1[C:28](O)=[O:29].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C([O-])(O)=O.[Na+]>CN(C=O)C.C(OCC)(=O)C>[Cl:22][C:23]1[N:24]=[CH:25][N:26]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:27]=1[C:28]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH3:10])=[C:5]([O:11][C:12]2[CH:13]=[C:14]([C:15]#[N:16])[CH:17]=[C:18]([Cl:20])[CH:19]=2)[C:4]=1[F:21])=[O:29]
Reactant: CCc1ccc(CN)c(F)c1Oc1cc(Cl)cc(C#N)c1
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)O
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CCc1ccc(CNC(=O)c2c(Cl)ncn2COCC[Si](C)(C)C)c(F)c1Oc1cc(Cl)cc(C#N)c1
Yield: 86.6 %

Procedure:
A solution of 3-{[3-(aminomethyl)-6-ethyl-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.075 g, 0.246 mmol), 4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (0.075 g, 0.271 mmol), EDC (0.052 g, 0.271 mmol) and HOBT (0.041 g, 0.271 mmol) in DMF (4 ml) was stirred at RT under an atmosphere of nitrogen for 16 h then ethyl acetate (100 mL) and saturated aqueous NaHCO3 solution (100 mL) were added. The organic layer was separated, washed with saturated aqueous NaHCO3 solution (100 mL), water (100 mL), dried over MgSO4, filtered and concentrated. The material was purified on silica gel (hexanes/ethyl acetate) to give the title compound (0.12 g, 74%) in ca. 85% purity. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.65 (s, 1H), 7.34 (t, 1H), 7.28-7.32 (m, 1H), 7.09-7.20 (m, 3H), 7.02 (d, 1H), 5.75 (s, 2H), 4.69 (d, 2H), 3.61 (t, 2H), 2.57 (q, 2H), 1.18 (t, 3H), 0.95 (t, 2H).
Reaction SMILES: [ClH:1].[CH2:2]([O:9][C:10](=[O:57])[NH:11][CH2:12][CH2:13][NH:14][C:15](=[O:56])[C@@H:16]([NH:30][C:31](=[O:55])[C@H:32]([CH2:41][CH2:42][CH2:43][NH:44][C:45]([O:47]CC1C=CC=CC=1)=[O:46])[NH:33]C(OC(C)(C)C)=O)[CH2:17][CH2:18][NH:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])C1C=CC=CC=1.O1[CH2:63][CH2:62]OCC1>>[ClH:1].[CH2:23]([N:44]([CH2:43][CH2:42][CH2:41][C@H:32]([NH2:33])[C:31](=[O:55])[NH:30][C@@H:16]([CH2:17][CH2:18][NH:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[C:15](=[O:56])[NH:14][CH2:13][CH2:12][NH:11][C:10](=[O:57])[O:9][CH2:2][C:63]1[CH:62]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:45](=[O:46])[OH:47])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)N[C@@H](CCNC(=O)OCc1ccccc1)C(=O)NCCNC(=O)OCc1ccccc1
Reactant: C1COCCO1
Agent: Cl
Product: N[C@@H](CCCN(Cc1ccccc1)C(=O)O)C(=O)N[C@@H](CCNC(=O)OCc1ccccc1)C(=O)NCCNC(=O)OCc1ccccc1
Reaction time: 4 h

Procedure:
3.7 ml of a 4M solution of hydrogen chloride in dioxane are added to a solution of 71 mg (0.091 mmol) of benzyl{2-[((2S)-4-{[(benzyloxy)carbonyl]amino}-2-{[N5-[(benzyloxy)carbonyl]-N2-(tert-butoxycarbonyl)-L-ornithyl]amino}butanoyl)amino]ethyl}carbamate (Example 112A) in 1.5 ml of dioxane at RT. After 4 h at RT, the reaction solution is concentrated in vacuo, coevaporated with dichloromethane several times and dried under high vacuum. The crude product is reacted without further purification.