Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:5]=[C:6]([CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[C:11]([OH:13])=[O:12])[CH:7]=[CH:8][CH:9]=1.[Li]CCCC.Br[CH2:33][C:34]1[N:39]=[CH:38][CH:37]=[CH:36][N:35]=1>C1COCC1>[N:35]1[CH:36]=[CH:37][CH:38]=[N:39][C:34]=1[CH2:33][C:10]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=1)([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:25])([F:26])[F:1])[CH:5]=1)[C:11]([OH:13])=[O:12]
Reactant: BrCc1ncccn1
Reactant: O=C(O)C(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)C(Cc1ncccn1)(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Temperature: -15 °C
Reaction time: 0.75 h

Procedure:
At −15° C. to a solution of 2,2-bis(3-(trifluoromethoxy)phenyl)acetic acid prepared as described in Procedure 73 (607 mg, 1.6 mmol) in THF (6 mL) was added nBuLi (1.6 mL, 2M in hexane, 3.2 mmol). The mixture was stirred at −15° C. for 45 min. 2-(Bromomethyl)pyrimidine (412 mg, crude) in THF (1 mL) was added and the reaction mixture was allowed to warm to rt and stirred for 18 h, then quenched with saturated NH4Cl. The aqueous layer was extracted with EtOAc (3×50 mL). The combined organic layer was dried over MgSO4, filtered and concentrated to give 3-(pyrimidin-2-yl)-2,2-bis(3-(trifluoromethoxy)phenyl)propanoic acid as a yellow solid (437 mg, 58% crude). This crude solid was carried onto the next step without further purification.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH2:17][OH:18])=[CH:7][CH2:6]2)[O:4]CC1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:8]12([CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]1)[C:11]1[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:17][O:18]2
Reactant: OCc1ccccc1C1=CCC2(CC1)OCCO2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CCC2(CC1)OCc1ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [2-(1,4-dioxa-spiro[4.5]dec-7-en-8-yl)-phenyl]-methanol (1 g, 4.06 mmol, as prepared in the previous step) in DCM (2 mL) was added TFA (8 mL) and stirred at RT, 2 hours followed by removal of solvent in vacuo to afford the title compound.
Reaction SMILES: [Cl-].[OH:2][C@H:3]([CH3:15])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1[NH3+:14].[N:16](OCCC(C)C)=O.O>ClCCl.C([O-])(=O)C.C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:13][O:12][C:10]1[CH:11]=[C:6]2[C:7](=[CH:8][CH:9]=1)[NH:14][N:16]=[C:5]2[CH2:4][C@H:3]([OH:2])[CH3:15]
Reactant: CC(C)CCON=O
Reactant: COc1ccc([NH3+])c(CC[C@@H](C)O)c1
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COc1ccc2[nH]nc(C[C@@H](C)O)c2c1
Reaction time: 2 h
Yield: 66.6 %

Procedure:
To a stirred suspension of the product from step C (2.66 g, 11.5 mmol) in dichloromethane (150 mL) at ambient temperature was added isoamyl nitrite (2.47 mL, 18.4 mmol, 1.6 equiv.). After 30 minutes tetrabutylammonium acetate (5.54 g, 18.4 mmol, 1.6 eq) was added and the mixture was stirred for 2 hours. Water was added to the mixture and the organic layer was separated and washed with 2 N NaOH and water. After drying and evaporation the crude product was purified by column chromatography (gradient of 20% to 40% ethyl acetate in hexane) to give an oil (1.58 g) that crystallized from ethyl acetate/hexane (1:1) to afford a solid (1.30 g, 55%): mp 89-91° C.; LC/MS (+APCI) m/z 207 (M+H).
Reaction SMILES: C([O:5][C:6](=[O:34])[CH2:7][C@@H:8]([CH2:28][C:29]1[N:30]=[CH:31][S:32][CH:33]=1)[C:9](N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)CC(C)C)=[O:10])(C)(C)C.[O:35]1CCNC1=O.[OH-].[Li+].OO>>[S:32]1[CH:33]=[C:29]([CH2:28][C@H:8]([CH2:7][C:6]([OH:5])=[O:34])[C:9]([OH:10])=[O:35])[N:30]=[CH:31]1
Reactant: O=C1NCCO1
Reactant: CC(C)C[C@H](O)[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@@H](CC(=O)OC(C)(C)C)Cc1cscn1
Agent: OO
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)C[C@@H](Cc1cscn1)C(=O)O

Procedure:
4-{[1(S)-(Cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]amino}-4-oxo-3(R)-(4-thiazolylmethyl)butanoic acid tert-butyl ester: The latter 2-oxazolidinone derivative (4.02 g, 10.5 mmol) was reacted with lithium hydroxide-hydrogen peroxide according to the procedure of example 2, section (g) to give the monoprotected dicarboxylic acid of formula 2, i.e. the 4-tert-butyl ester of 2(R)-(4-thiazolylmethyl)butanedioic acid. Subsequent coupling of the latter compound (2.83 g, 10.4 mmol) with 2(S)-amino-1-cyclohexyl-6-methyl-3(R),4(S)-heptanediol hydrochloride (3.21 g, 11.5 mmol) according to the coupling procedure of example 2, section (g) gave the desired protected amido acid as a white solid (3.75 g, 72%); 1H NMR(CDCl3) δ8.70 (s, 1H), 7.10 (s,1H), 5.96 (d, J=8.3 Hz,1H), 4.40-4.25 (m,2H), 3.40-2.70 (m,6H), 2.40 (dd, J=4.4 Hz,16.8 Hz,1H), 1.95-1.10 (m,17H), 1.40 (s,9H), 0.90 (d, J=6.6 Hz,3H), 0.80 (d, J=6.4 Hz,3H).
Reaction SMILES: [CH2:1]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH3:15])[CH:11]=2)[C:6]1=[O:16])[CH2:2][CH2:3][CH3:4].N12CCCN=C1CCCCC2.[CH:28]([C:30]([CH2:32][CH3:33])=[O:31])=[CH2:29]>O1CCCC1>[CH2:1]([C:5]1([CH2:29][CH2:28][C:30](=[O:31])[CH2:32][CH3:33])[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH3:15])[CH:11]=2)[C:6]1=[O:16])[CH2:2][CH2:3][CH3:4]
Reactant: C=CC(=O)CC
Reactant: CCCCC1Cc2cc(OC)ccc2C1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCCCC1(CCC(=O)CC)Cc2cc(OC)ccc2C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 27.8 %

Procedure:
A solution of crude 2-butyl-5-methoxy-1-indanone (218 mg, 1 mmol) in tetrahydrofuran (THF, 2 mL) was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.030 mL, 0.2 mmol) and ethyl vinyl ketone (EVK, 0.200 mL, 2 mmol). The resulting solution was stirred under a nitrogen atmosphere at room temperature for 16 hours, followed by heating in an oil bath at 60° C. for 24 hours. Evaporation of the solvent under vacuum left a residue that was shown by NMR to be approximately a 1:1 mixture of starting material and product. The residue was purified by preparative layer chromatography on three 0.1×20×20 cm silica gel GF plates using 5% EtOAc in CH2Cl2 as developing solvent. The product band was eluted with EtOAc to provide 2-butyl-5-methoxy-2-(3-oxo-pentyl)-1-indanone (84 mg) as an oil.
Reaction SMILES: [OH:1][CH:2]([C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=1)[CH2:3][CH2:4][CH3:5].Cl[O-].[Na+].N1C=CC=CC=1.Cl>ClCCl>[C:2]([C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=1)(=[O:1])[CH2:3][CH2:4][CH3:5]
Reactant: CCCC(O)c1cc(-c2ccccc2)no1
Agent: Cl
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC(=O)c1cc(-c2ccccc2)no1
Temperature: 20 °C

Procedure:
In 12.5 ml of dichloromethane, 4.4 g (20 mmol) of 5-(1-hydroxybutyl)-3-phenylisoxazole were dissolved. While the solution was being stirred, 35.2 g (60 mmol) of a 12.7% aqueous solution of sodium hypochlorite were added dropwise to the solution. Next, a liquid mixture which had been obtained by adding 0.48 g (6.1 mmol) of pyridine to 1.0 ml of 6 N hydrochloric acid) was added dropwise over 1 hour and the reaction temperature was maintained at 20° C. After completion of the reaction, the organic layer was collected and was washed successively with a 5% aqueous solution of sodium hydrogensulfite, water and 1 N hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was then recrystallized from ethanol, whereby the target compound, namely, 5-butyryl-3-phenylisoxazole was obtained as crystals.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[C:5]([CH2:15][CH3:16])[CH:4]=1)#[N:2].CCN(CC)CC.Cl.[NH2:25][OH:26]>CCO>[CH2:15]([C:5]1[CH:4]=[C:3]([C:1](=[NH:2])[NH:25][OH:26])[CH:8]=[C:7]([CH3:9])[C:6]=1[CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH3:16]
Reactant: NO
Reactant: CCc1cc(C#N)cc(C)c1CCC(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCc1cc(C(=N)NO)cc(C)c1CCC(=O)O
Temperature: 25 °C
Yield: 101.6 %

Procedure:
To a solution of 3-(4-cyano-2-ethyl-6-methyl-phenyl)-propionic acid (10.0 g, 46.0 mmol) in EtOH (80 mL), NEt3 (13.97 g, 138.1 mmol) followed by hydroxylamine hydrochloride (6.40 g, 92.1 mmol) is added. The mixture is refluxed for 7 h before it is cooled to rt. The solvent is removed in vacuo. The residue is dissolved in 2 N aq. HCl and the pH is adjusted to 5 by adding 32% aq. NaOH solution. The precipitate that forms is collected, washed with water and dried under high vacuum at 40° C. for 18 h to give 3-[2-ethyl-4-(N-hydroxycarbamimidoyl)-6-methyl-phenyl]-propionic acid (11.7 g) as a beige crystalline powder; LC-MS: tR=0.60 min, [M+1]+=251.09.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4]1.S=[C:10]1[CH2:14][S:13][C:12](=[O:15])[NH:11]1>C(O)C>[OH:8][CH2:7][C:3]1([CH2:2][NH:1][C:10]2[CH2:14][S:13][C:12](=[O:15])[N:11]=2)[CH2:6][CH2:5][CH2:4]1
Reactant: O=C1NC(=S)CS1
Reactant: NCC1(CO)CCC1
Solvent: CCO
Product: O=C1N=C(NCC2(CO)CCC2)CS1
Yield: 42.7 %

Procedure:
To a solution of [1-(aminomethyl)cyclobutyl]methanol (1.00 g) in ethanol (30 mL) was added 4-thioxo-1,3-thiazolidin-2-one (1.16 g), and the mixture was heated under reflux overnight. The reaction mixture was concentrated under reduced pressure, and the obtained powder was washed with ethyl acetate to give the title compound (795 mg).
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:15]([O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[O:16])[CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)[CH3:2].O[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:27][CH:26]=1.C(OC(=O)C(OCC)CC1C=CC(OC(=O)CC2N=C(C3C=CC=CC=3)OC=2C)=C(CC2C=CC=CC=2)C=1)C1C=CC=CC=1>>[CH3:35][S:32]([O:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][O:11][C:10](=[O:12])[C:9]2[CH:13]=[CH:14][C:6]([CH2:5][CH:4]([O:3][CH2:1][CH3:2])[C:15]([O:17][CH2:18][C:19]([Cl:20])([Cl:21])[Cl:22])=[O:16])=[CH:7][CH:8]=2)=[CH:26][CH:27]=1)(=[O:34])=[O:33]
Reactant: CCOC(Cc1ccc(C(=O)O)cc1)C(=O)OCC(Cl)(Cl)Cl
Reactant: CS(=O)(=O)Oc1ccc(CO)cc1
Agent: CCOC(Cc1ccc(OC(=O)Cc2nc(-c3ccccc3)oc2C)c(Cc2ccccc2)c1)C(=O)OCc1ccccc1
Product: CCOC(Cc1ccc(C(=O)OCc2ccc(OS(C)(=O)=O)cc2)cc1)C(=O)OCC(Cl)(Cl)Cl
Yield: 47 %

Procedure:
The title compound was prepared from 4-[2-ethoxy-2-(2,2,2-trichloro-ethoxy carbonyl)-ethyl]-benzoic acid (0.032 g, 0.087 mmol) and methanesulfonic acid 4-hydroxymethyl-phenyl ester (0.018 g, 0.09 mmol) in the same manner as described for 3-{3-benzyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-acetoxy]-phenyl}-2-ethoxy-propionic acid benzyl ester. The crude product was purified by column chromatography using n-heptane/EtOAc (2:3) as the eluent to afford the title compound as a solid (0.023, 47%). 1H NMR (400 MHz, CDCl3): δ 7.96-7.98 (d, 2H), 7.47-7.49 (d, 2H), 7.33-7.35 (d, 2H), 7.27-7.29 (d, 2H), 5.33 (s, 2H), 4.68-4.81 (q, 2H), 4.15 (m, 1H), 3.65 (m, 1H), 3.32 (m, 1H), 3.08-3.15 (m, 2H), 3.13 (s, 3H), 1.13 (t, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=2[OH:20])[N:3]=1.[OH:21][C@H:22]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24].C(N(CC)CC)C>C(Cl)Cl>[F:19][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([OH:20])[C:13]=1[C:4]1[N:3]=[C:2]([N:28]2[CH2:27][CH2:26][N:25]([C:23](=[O:24])[C@H:22]([OH:21])[CH2:31][CH:32]([CH3:33])[CH3:34])[CH2:30][CH2:29]2)[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=1
Reactant: Cc1ccc2c(Cl)nc(-c3c(O)cccc3F)nc2c1
Reactant: CC(C)C[C@@H](O)C(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2c(N3CCN(C(=O)[C@H](O)CC(C)C)CC3)nc(-c3c(O)cccc3F)nc2c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
2-(4-Chloro-7-methylquinazolin-2-yl)-3-fluorophenol (300 mg, 1.04 mmol) in CH2Cl2 (5 mL) was cooled using an ice water batch. To this stirring solution was added (R)-2-hydroxy-4-methyl-1-(piperazin-1-yl)pentan-1-one (312 mg, 1.56 mmol), followed by triethylamine (210 mg, 291 μL, 2.08 mmol). After letting the reaction warn to room temperature, it was stirred overnight. The mixture was partitioned between water and CH2Cl2 and separated, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered, and concentrated to a viscous yellow oil. Purification via silica gel chromatography using 0-30% EtOAc in CH2Cl2/hexanes (2:1) gave (R)-1-(4-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4-methylpentan-1-one as a bright yellow foam/solid. (413 mg, 88%). LC/MS: m/z 453.1 (M+H)+ at 2.44 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) d 8.01 (d, J=8.5 Hz, 1H), 7.68 (s, 1H), 7.42 (d, J=8.5 Hz, 1H), 7.37-7.32 (m, 1H), 6.80 (d, J=8.3 Hz, 1H), 6.76-6.71 (m, 1H), 4.91 (d, J=7.2 Hz, 1H), 4.40-4.35 (m, 1H), 4.02-3.65 (m, 8H), 2.52 (s, 3H), 1.82-1.73 (m, 1H), 1.47-1.34 (m, 2H), 0.91 (dd, J=6.5, 4.1 Hz, 6H) ppm.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N+:5]=1[O-:10])[CH2:2][CH3:3].[N+:11]([O-])([OH:13])=[O:12].C(=O)([O-])[O-].[Na+].[Na+]>S(=O)(=O)(O)O>[N+:11]([C:8]1[CH:7]=[CH:6][N+:5]([O-:10])=[C:4]([CH2:1][CH2:2][CH3:3])[CH:9]=1)([O-:13])=[O:12]
Reactant: CCCc1cccc[n+]1[O-]
Reactant: O=[N+]([O-])O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCCc1cc([N+](=O)[O-])cc[n+]1[O-]
Temperature: 71 °C
Yield: 49 %

Procedure:
A mixture of 2-n-propylpyridine-N-oxide (137.2 g, 1.0 mol) in 200 ml of sulfuric acid (sp.gr. 1.84) was stirred in an ice-salt bath and 320 ml of nitric acid (sp.gr. 1.52) was added. The mixture was carefully heated to 70-72° C. and reacted for 22 hours. The reaction mixture was cooled and poured onto ice and, with stirring, neutralized with portions of sodium carbonate (500 g). The resulting precipitate was collected, washed with water and dried. The dried substance was slurried in 1 liter of dichloromethane and anhydrous sodium sulfate was added. The mixture was filtered and the solvent was evaporated. The yellow residue from evaporation of the dichloromethane solution was dried to afford 89.2 g (49%) of 4-nitro-2-n-propylpyridine-N-oxide. M.p. 89-91° C. 1H-NMR (CDCl3, 200 MHz) δ: 1.10 (t, 3H), 1.70 (sext, 2H), 2.94 (t, 2H), 7.96 (dd, 1H), 8.08 (dd, 1H), 8.30 (dd, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][C:11]([CH3:20])([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:10][C:9]2=[O:21])[CH:5]=[CH:6][CH:7]=1.[N:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[CH3:20][C:11]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:10][C:9](=[O:21])[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:25]3[CH:26]=[CH:27][N:22]=[CH:23][CH:24]=3)[CH:3]=2)[CH2:13][CH2:12]1
Reactant: OB(O)c1ccncc1
Reactant: CC1(c2ccccc2)CCN(c2cccc(Br)c2)C(=O)O1
Product: CC1(c2ccccc2)CCN(c2cccc(-c3ccncc3)c2)C(=O)O1

Procedure:
The title compound was prepared from 3-(3-bromophenyl)-6-methyl-6-phenyl-1,3-oxazinan-2-one and 4-pyridylboronic acid following procedures analogous to those in Example 1 Step 2. LC-MS Method 2, tR=1.329 min, m/z=345.1. 1H NMR (CDCl3) 1.70 (s, 3H), 2.30-2.50 (m, 2H), 3.30 (m, 1H), 3.50 (m, 1H), 4.10 (m, 2H), 7.27-7.50 (m, 9H), 8.60 (b, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][NH:14][C:13](=[O:17])[C@H:12]2[CH2:18][C:19]([NH:21][C@H:22]2[C:31]3[C:26](=[CH:27][C:28]([CH2:32][CH:33]=O)=[CH:29][CH:30]=3)[CH2:25][CH2:24][CH2:23]2)=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][NH:14][C:13](=[O:17])[C@H:12]2[CH2:18][C:19]([NH:21][C@H:22]2[C:31]3[C:26](=[CH:27][C:28]([CH2:32][CH2:33][N:35]4[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]4)=[CH:29][CH:30]=3)[CH2:25][CH2:24][CH2:23]2)=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C1CCNCC1
Reactant: O=CCc1ccc2c(c1)CCC[C@H]2NC(=O)C[C@@H]1C(=O)NCCN1S(=O)(=O)c1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C(C[C@@H]1C(=O)NCCN1S(=O)(=O)c1ccc(Cl)cc1)N[C@@H]1CCCc2cc(CCN3CCCCC3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product from step E (63 mg, 0.116 mmol) and piperidine (20 mg, 0.23 mmol) in 1 mL of dichloroethane was added sodium triacetoxyborohydride (49 mg, 0.23 mmol). After stirring overnight at room temperature, the reaction solution was diluted with EtOAc and washed with sat. NaHCO3 and brine. The organic phase was dried over Na2SO4 and evaporated to dryness in vaco. Flash chromatography (SiO2, EtOAc to EtOAc/MeOH=100:10 to 100:12) afforded the title compound as a white solid. MS: 573.2 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2.[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17]Br.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2
Reactant: O=C1NCCc2cc(O)ccc21
Reactant: Fc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1NCCc2cc(OCc3cccc(F)c3)ccc21
Temperature: 90 °C
Yield: 87.6 %

Procedure:
A mixture of 6-hydroxy-3,4-dihydro-2H-isoquinolin-1-one (0.400 g, 2.44 mmol), 3-fluorobenzyl bromide (0.509 g, 2.69 mmol), potassium carbonate (0.372 g, 2.69 mmol) and N,N-dimethylformamide (5 ml) was heated to 90° C. for 8 h. Water was added and the resulting precipitate was washed with diethylether and then dried under high vacuum to afford the title compound (0.580 g, 87%). MS: m/e=272.3 (M+H+).
Reaction SMILES: [CH2:1]([O:8][N:9]([CH2:12][C:13]1([C:20]([OH:22])=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:23]([C:25]1[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=1)[NH2:24].CN1CCOCC1.C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[CH2:1]([O:8][N:9]([CH2:12][C:13]1([C:20]([NH:24][NH:23][C:25]2[N:30]=[C:29]([C:31]([F:33])([F:32])[F:34])[CH:28]=[CH:27][N:26]=2)=[O:22])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)[CH:10]=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NNc1nccc(C(F)(F)F)n1
Reactant: O=CN(CC1(C(=O)O)CCCCCC1)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=CN(CC1(C(=O)NNc2nccc(C(F)(F)F)n2)CCCCCC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.6 %

Procedure:
To a mixture of 1-[(Benzyloxy-formyl-amino)-methyl]-cycloheptanecarboxylic acid (0.10 g, 0.33 mmol), 2-hydrazino-4-(trifluoromethyl)pyrimidine (0.07 g, 0.39 mmol), NMM (0.10 g, 1.0 mmol) and HOAt (0.053 g, 0.39 mmol) in DMF (1 mL) at room temperature was added 1-[3-(dimethylamino)-propyl]-3-ethylcarbodiimide hydrochloride (0.075 g, 0.34 mmol). After stirring at room temperature 18 h, the reaction mixture was then purified by preparative, reverse-phase HPLC to afford the title compound as a white solid (0.11 g, 72%). MH+466.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].O1CCCC1.[CH3:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][C:22]=1[N+:28]([O-:30])=[O:29]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:25][C:24]2[CH:26]=[CH:27][C:21]([CH3:20])=[C:22]([N+:28]([O-:30])=[O:29])[CH:23]=2)=[O:10])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.3 %

Procedure:
1-Chloro-4-isocyanato-2-(trifluoromethyl)benzene (9.97 g, 45.0 mmol) was stirred in a solvent of tetrahydrofuran (100 mL). The reaction solution was added with 4-methyl-3-nitroaniline (6.52 g, 42.9 mmol), followed by stirring for about 6 hours at room temperature. The reaction mixture was diluted with ethyl acetate, and washed with a saturated aqueous sodium bicarbonate solution and saline. The organic layer thus obtained was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrated solid was added with a mixed solution of ethyl acetate/hexane (1/5), followed by stirring for 2 hours or more. The resulting solid was filtered under reduced pressure, and washed with diethyl ether. The filtered solid was dried with warm wind in an oven (40° C.) for 3 hours or more to obtain the title compound (14 g, 87%).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([C:23]#[N:24])[CH2:6][CH:7]1[C:12](=O)[CH2:11][CH2:10][CH:9]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:8]1)C.C([O-])(=O)C.[NH4+:30]>CO.O>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][CH:9]2[CH2:10][CH2:11][C:12]3[NH:30][C:4](=[O:3])[CH:5]([C:23]#[N:24])[CH2:6][C:7]=3[CH2:8]2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)C(C#N)CC1CC(Cc2ccc(OC)cc2)CCC1=O
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CO
Solvent: O
Product: COc1ccc(CC2CCC3=C(C2)CC(C#N)C(=O)N3)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Cyano-3-[3-(4-methoxyphenyl)methyl-6-oxocyclohexanyl]propanoic acid ethyl ester (1 g) (prepared as described in Example 5(a)) in methanol (10 ml) was treated with ammonium acetate (2.2 g) and left to stir at room temperature for 2 hours. The reaction mixture was diluted with water and a solid crystallised out. The solid was mixed with water and methanol, and the methanol removed under reduced pressure. The mixture was extracted into ethyl acetate, dried (MgSO4), and solvent evaporated to give the title compound as the quarterhydrate, mp 158°-9° C.
Reaction SMILES: C([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([C:20](=[O:24])[CH:21](O)O)=[CH:11][CH:10]=1)C1C=CC=CC=1.[F:25][C:26]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:27]=1[CH2:28][C:29]1([NH2:32])[CH2:31][CH2:30]1.FC(F)(F)C([O-])=O>>[F:25][C:26]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:27]=1[CH2:28][C:29]1([NH:32][CH2:21][CH:20]([C:12]2[C:13]3[O:18][CH2:17][C:16](=[O:19])[NH:15][C:14]=3[C:9]([OH:8])=[CH:10][CH:11]=2)[OH:24])[CH2:30][CH2:31]1
Reactant: O=C1COc2c(C(=O)C(O)O)ccc(OCc3ccccc3)c2N1
Reactant: NC1(Cc2c(F)cccc2F)CC1
Agent: O=C([O-])C(F)(F)F
Product: O=C1COc2c(C(O)CNC3(Cc4c(F)cccc4F)CC3)ccc(O)c2N1

Procedure:
Prepared according to general method 3 from 329 mg (1 mmol) 5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and 183 mg (1 mmol) 1-(2,6-difluoro-benzyl)-cyclopropylamine. Yield: 108 mg (21%, trifluoroacetate); mass spectroscopy: [M+H]+=391.