Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C@@H](PC)[C]1[C](P(C2C3C(=CC=CC=3)C=CC=2)C2C3C(=CC=CC=3)C=CC=2)[CH][CH][CH]1.[CH2:31]([C:38]1[C:47]2[C:42](=[CH:43][CH:44]=[C:45]([O:48][CH3:49])[CH:46]=2)[CH2:41][CH2:40][C:39]=1[NH:50][C:51](=[O:54])[CH2:52][CH3:53])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[H][H]>[Rh+].ClC1CCCCC=CC=1.CO>[CH2:31]([C@@H:38]1[C:47]2[C:42](=[CH:43][CH:44]=[C:45]([O:48][CH3:49])[CH:46]=2)[CH2:41][CH2:40][C@@H:39]1[NH:50][C:51](=[O:54])[CH2:52][CH3:53])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCC(=O)NC1=C(Cc2ccccc2)c2cc(OC)ccc2CC1
Reactant: [H][H]
Agent: [Rh+]
Agent: CP[C@H](C)[C]1[CH][CH][CH][C]1P(c1cccc2ccccc12)c1cccc2ccccc12
Agent: ClC1=CC=CCCCC1
Solvent: CO
Product: CCC(=O)N[C@H]1CCc2ccc(OC)cc2[C@H]1Cc1ccccc1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 96.6 %

Procedure:
Chlorocyclooctadiene rhodium(I) dimer (0.802 g, 1.63 mmol, 3.25 mmol of Rh), Josiphos SL-J216-2 (2.199 g, 3.42 mmol), and N-(1-benzyl-7-methoxy-3,4-dihydronaphthalen-2-yl)propionamide (440 g, 1.37 mol) were combined in a metal reactor, and the vessel was inerted with argon. Degassed methanol (4.40 I) was added, then the mixture was stirred under argon at 50° C. for 20 min. The vessel was pressurized with 60 psig of hydrogen and stirred at 55° C. for 40 hrs. HPLC analysis indicated complete conversion and 95.9% ee. The methanol solution of crude reduction product was concentrated and triturated with heptane to yield 428.2 g (yield: 91%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:11].C(=O)([O-])[O-].[K+].[K+].[CH3:18][CH:19](Br)[C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[CH:22][C:21]=1[N+:30]([O-:32])=[O:31].[O-]S([O-])(=O)=O.[Mg+2]>C([O-])(O)=O.[Na+].CCOCC.CN(C=O)C>[CH3:18][CH:19]([O:1][C:2]1[C:3]([CH3:11])=[CH:4][C:5]([CH:6]=[O:7])=[CH:8][C:9]=1[CH3:10])[C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[CH:22][C:21]=1[N+:30]([O-:32])=[O:31]
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: COc1cc(C(C)Br)c([N+](=O)[O-])cc1OC
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1cc(C(C)Oc2c(C)cc(C=O)cc2C)c([N+](=O)[O-])cc1OC
Reaction time: 44 h
Yield: 60 %

Procedure:
DMF (5 mL) at r.t. was added to a stirring mixture of 4-hydroxy-3,5-dimethylbenzaldehyde (116 mg, 0.78 mmol), potassium carbonate (214 mg, 1.55 mmol) and a-methyl-2-nitro-4,5-dimethoxybenzyl bromide (169 mg, 0.58 mmol) and stirring was continued for 44 hours. The reaction was diluted with 5% NaHCO3 (100 mL) and aqueous workup (Et2O, MgSO4) followed by concentration in vacuo yielded a yellow oil which was purified by flash chromatography (20 g, 5:1 hexanes/ethyl acetate) to yield 7e (125 mg, 60%) as a yellow oil: 1H NMR (270 MHz, CDCl3) d 1.56 (d, J=6.2 Hz, 3H), 2.22 (s, 6H), 3.92 (s, 3H), 4.01 (s, 3H), 5.83 (q, J=6.2 Hz, 1H), 7.49 s, 3H), 7.57 (s, 1H), 9.81 (s, 1H); 13C NMR (68 MHz, CDCI3) d 17.6, 23.5, 56.4, 56.5, 76.6, 107.5, 109.0, 131.1, 131.7, 132.1, 134.5, 139.0, 148.1, 153.8, 160.5, 191.5.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([OH:21])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][N:24]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][N:24]=1)=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C1CCCc2c(OCc3ccccc3)cccc21
Reactant: Cc1ccc(N)nc1
Product: Cc1ccc(NC(=O)C2CCCc3c(OCc4ccccc4)cccc32)nc1
Yield: 53.8 %

Procedure:
By the reaction and treatment in the same manner as in Preparation Example 11 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (2.82 g) and 2-amino-5-methylpyridine (1.08 g) as starting materials, 5-benzyloxy-N-(5-methylpyridin-2-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (2.00 g) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][CH:10]([C:18]2[CH:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([NH:32][CH2:33][C:34]([OH:36])=[O:35])=[O:31])[CH:25]=3)[CH:21]=[CH:22][CH:23]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.Cl.[NH2:39][OH:40].C([O-])(O)=O.[Na+]>>[OH:40]/[N:39]=[C:8](/[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1)\[CH2:9][CH:10]([C:18]1[CH:19]=[C:20]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([NH:32][CH2:33][C:34]([OH:36])=[O:35])=[O:31])[CH:25]=2)[CH:21]=[CH:22][CH:23]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: NO
Reactant: Cc1cc(C(=O)CC(c2cccc(-c3cccc(C(=O)NCC(=O)O)c3)c2)c2ccccc2C)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(CC(c2cccc(-c3cccc(C(=O)NCC(=O)O)c3)c2)c2ccccc2C)=N/O)ccn1

Procedure:
In analogy to example 74, step 4, from ({3′-[3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-biphenyl-3-carbonyl}-amino)-acetic acid and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound which precipitated as a white solid on work up, MS (ESI−): m/z=506.2 ([M−H]−).
Reaction SMILES: [OH-:1].[K+].[O:3]([C:10]1[CH:20]=[CH:19][CH:18]=[CH:17][C:11]=1[C:12]([C:15]#[N:16])=[N:13][OH:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>C(O)(C)(C)C>[O:3]([C:10]1[CH:20]=[CH:19][CH:18]=[CH:17][C:11]=1[C:12](=[N:13][OH:14])[C:15]([NH2:16])=[O:1])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: N#CC(=NO)c1ccccc1Oc1ccccc1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Product: NC(=O)C(=NO)c1ccccc1Oc1ccccc1
Yield: 67.5 %

Procedure:
85% Potassium hydroxide (2.57 g, 38.9 mmol) and tert-butyl alcohol (40 ml) were added to 2-phenoxy-α-hydroxyiminobenzyl cyanide (E/Z=11/89)(3.10 g, 13 mmol). The mixture was heated under reflux for 10 hours. After completion of the reaction, the reaction mixture was neutralized with 1N hydrochloric acid, extracted with ethyl acetate (100 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting crystals were recrystallized from n-hexane/ethyl acetate to give 2-(2-phenoxyphenyl)-2-hydroxyiminoacetamide (2.25 g, Yield: 67.5%, Z=at least 98%) as pale yellow crystals.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]4[CH:30]=[C:29]5[C:24]([CH:25]=[CH:26][C:27](=[O:31])[NH:28]5)=[CH:23][CH:22]=4)[CH2:12][CH2:11]3)=[CH:7][CH:8]=[CH:9][C:2]1=2.C(N(CC)CC)C.[C:39](Cl)(=[O:51])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50].O>ClCCl>[C:39]([O:31][C:27]1[CH:26]=[CH:25][C:24]2[C:29](=[CH:30][C:21]([O:20][CH2:19][CH2:18][CH2:17][CH2:16][N:13]3[CH2:12][CH2:11][N:10]([C:6]4[C:3]5[CH:4]=[CH:5][S:1][C:2]=5[CH:9]=[CH:8][CH:7]=4)[CH2:15][CH2:14]3)=[CH:22][CH:23]=2)[N:28]=1)(=[O:51])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50]
Reactant: O=c1ccc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc2[nH]1
Reactant: CCCCCCCCCCCC(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC(=O)Oc1ccc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc2n1

Procedure:
To a solution of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one (800 mg) in dichloromethane (20 ml) synthesized in the same manner as in WO2006/112464 (Example 1) was added triethylamine (0.77 ml), with stirring under ice-cooling, dodecanoylchloride (1.1 ml) was added and the mixture was stirred at room temperature for 4 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate) to give 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-quinolin-2-yl dodecanoate (1.34 g).
Reaction SMILES: [CH3:1][Mg]Br.[Br:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[CH:11]=[O:12]>C1COCC1>[Br:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[CH:11]([OH:12])[CH3:1]
Reactant: C[Mg]Br
Reactant: O=Cc1ccncc1Br
Solvent: C1CCOC1
Product: CC(O)c1ccncc1Br
Temperature: 0 °C

Procedure:
A solution of methylmagnesium bromide (10.00 ml, 30.0 mmol) was added dropwise to a solution of 3-Bromo-pyridine-4-carbaldehyde (1.860 g, 10.00 mmol) in THF (30 mL) at −78° C. The resulting mixture was slowly warmed up to 0° C. over 3 h of period. The reaction was quenched by saturated NH4Cl solution. After extraction with ethyl acetate (50 mL×4), the combined extracts were dried over Na2SO4. After filtration and concentration, an oil residue was obtained, which turned into solid after standing (2.1 g). 1H NMR (400.3 MHz, CDCl3): δ 0.23 (d, J=8 Hz, 3H), 3.91 (m, 1H), 6.29 (d, J=4 Hz, 1H), 7.26 (d, J=4 Hz, 1H), 7.37 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[NH:14][CH2:15][C:16]1[O:17][CH:18]=[CH:19][N:20]=1.[CH3:21][S:22]([C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[C:28](O)=[O:29])(=[O:24])=[O:23]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:14]([CH2:15][C:16]1[O:17][CH:18]=[CH:19][N:20]=1)[C:28](=[O:29])[C:27]1[CH:31]=[C:32]([C:34]([F:37])([F:35])[F:36])[CH:33]=[C:25]([S:22]([CH3:21])(=[O:24])=[O:23])[CH:26]=1
Reactant: Clc1ccccc1-c1ccncc1NCc1ncco1
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Product: CS(=O)(=O)c1cc(C(=O)N(Cc2ncco2)c2cnccc2-c2ccccc2Cl)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from [4-(2-chloro-phenyl)-pyridin-3-yl]-oxazol-2-ylmethyl-amine and 3-(methylsulfonyl)-5-(trifluoromethyl)benzoic acid (example 114, intermediate a) after a reaction time of 21 hours at room temperature. The compound was purified by silica gel chromatography on a 20 g column using an MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). The product was purified by preparative HPLC (Gemini NX column) with a gradient of MeOH:water (containing 0.05% formic acid) (80:20 to 98:2). Colorless solid (157 mg, 42%). MS (ESI): m/z=536.065 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C:4]1[CH:9]=[C:8]([O:10][CH:11]([CH3:13])[CH3:12])[CH:7]=[C:6]([C:14](=O)[C:15]2[CH:20]=[CH:19][C:18]([P:21]([O:27][CH:28]([CH3:30])[CH3:29])([O:23][CH:24]([CH3:26])[CH3:25])=[O:22])=[CH:17][CH:16]=2)[CH:5]=1.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3](=[O:32])[C:4]1[CH:9]=[C:8]([O:10][CH:11]([CH3:12])[CH3:13])[CH:7]=[C:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([P:21]([O:23][CH:24]([CH3:26])[CH3:25])([O:27][CH:28]([CH3:29])[CH3:30])=[O:22])=[CH:17][CH:16]=2)[CH:5]=1
Reactant: COC(=O)c1cc(OC(C)C)cc(C(=O)c2ccc(P(=O)(OC(C)C)OC(C)C)cc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(Cc2ccc(P(=O)(OC(C)C)OC(C)C)cc2)cc(OC(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
To a solution of 3-[4-(diisopropoxy-phosphoryl)-benzoyl]-5-isopropoxy-benzoic acid methyl ester (750 mg, 1.62 mmol) in MeOH (30 mL) was added NaBH4 (120 mg, 3.17 mmol) at rt. Stirred at rt overnight. On the second day, the mixture was concentrated. The residue was partitioned between EOAc/HCl (0.1 M) and the organic layer was separated, washed with brine, dried, and concentrated. The resulting residue was dissolved in a mixture of EOAc/EtOH (20 mL, v/v=10:1) and hydrogenated over Pd/C (10%, 200 mg) using a Parr apparatus overnight. Then the mixture was filtered through a Celite plug. The filtrate was concentrated, azeotroped with CH2Cl2 to give the title compound (720 mg, 100%). 1H NMR (300 MHz, CDCl3): δ 7.72 (dd, J=13.8 Hz, 2H), 7.45 (m, 1H), 7.40 (m, 1H), 7.25 (dd, J=8, 4 Hz, 2H), 6.87 (m, 1H), 4.62-4.70 (m, 2H), 4.53-4.61 (m, 1H), 3.88 (s, 3H), 1.36 (d J=6 Hz, 6H), 1.32 (d J=6 Hz, 6H), 1.22 (d, J=6 Hz, 12H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:26])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)[O:11][C:6]=2[C:5]([F:27])=[CH:4][C:3]=1[F:28].[H-].[Na+].I[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].[Cl-].[NH4+]>CN(C)C=O>[F:28][C:3]1[CH:4]=[C:5]([F:27])[C:6]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)=[CH:9][C:8](=[O:26])[C:7]=2[C:2]=1[NH:1][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Reactant: CCCCCCI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCCCCCNc1c(F)cc(F)c2oc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)cc(=O)c12
Reaction time: 0.5 h
Yield: 79 %

Procedure:
505 mg (1.29 mmol) of 5-amino-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-4H-1-benzopyran-4-one was dissolved in 15 ml of dimethylformamide under argon atmosphere, 156 mg of sodium hydride (60% oil dispersion) and 0.38 ml of 1-iodohexane were added under ice-cooling and the mixture was stirred at the same temperature for 30 minutes. 0.19 ml of 1-iodohexane was added and the mixture was stirred for additional 2 hours. An aqueous saturated solution of ammonium chloride was added to the reaction solution and the mixture was extracted twice with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1) to give 487 mg (79%) of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-hexylamino-4H-1-benzopyran-4-one.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C@H:12]3[C@@:14]4([C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[NH:16][C:15]4=[O:23])[CH2:13]3)=[CH:9][CH:10]=2)[NH:5][N:4]=1)=[CH2:2].Br[C:25]1[C:26]([CH3:32])=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=1.CCN(C(C)C)C(C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:32][C:26]1[C:25](/[CH:2]=[CH:1]/[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C@H:12]4[C@@:14]5([C:22]6[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=6)[NH:16][C:15]5=[O:23])[CH2:13]4)=[CH:9][CH:10]=3)[NH:5][N:4]=2)=[CH:30][CH:29]=[C:28]([CH3:31])[N:27]=1
Reactant: Cc1ccc(Br)c(C)n1
Reactant: C=Cc1n[nH]c2cc([C@@H]3C[C@@]34C(=O)Nc3ccccc34)ccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(/C=C/c2n[nH]c3cc([C@@H]4C[C@@]45C(=O)Nc4ccccc45)ccc23)c(C)n1
Yield: 28.3 %

Procedure:
To a mixture of (1R*,2S*)-2-(3-vinyl-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-one (60 mg, 0.2 mmol) and 3-bromo-2,6-dimethylpyridine (37 mg, 0.2 mmol) in DMF (1.5 mL) was added iPr2NEt (0.07 mL), followed by Pd(OAc)2 (2.2 mg, 0.01 mmol) and P(o-tol)3 (6.7 mg, 0.022 mmol). The resulting mixture was purged with argon, and then microwaved 2 h at 125° C. Purification by prep-HPLC gave the title compound as a light yellow solid (23 mg, 22%). NMR indicated 3% of the branched isomer. 1H NMR (400 MHz, CD3OD) δ 8.73 (d, J=8.0 Hz, 1H), 7.97 (d, J=8.4 Hz, 1H), 7.72 (d, J=8.4 Hz, 1H, partially overlapping with the peak at 7.68 ppm), 7.68 (d, J=16.4 Hz, 1H, partially overlapping with the peak at 7.72 ppm), 7.59 (d, J=16.4 Hz, 1H), 7.50 (s, 1H), 7.06 (d, J=8.8 Hz, 1H, overlapping with the peak at 7.05 ppm), 7.05 (t, J=8.6 Hz, 1H, partially overlapping with the peak at 7.06 ppm), 6.94 (d, J=8.0 Hz, 1H), 6.56 (t, J=7.6 Hz, 1H), 5.98 (d, J=7.6 Hz, 1H), 3.35 (t, J=8.4 Hz, 1H), 2.86 (s, 3H), 2.76 (s, 3H), 2.24 (dd, J=7.6 Hz, 4.8 Hz, 1H), 2.18 (dd, J=9.0 Hz, 5.0 Hz, 1H); MS ESI 407.2 [M+H]+, calcd for [C26H22N4O+H]+ 407.2.
Reaction SMILES: FC(F)(F)C(O)=O.[SH:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1.O[CH:20]([C:27]1[C:32]([O:33][CH3:34])=[CH:31][C:30]([O:35][CH3:36])=[CH:29][C:28]=1[O:37][CH3:38])[CH2:21][N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1>>[CH3:38][O:37][C:28]1[CH:29]=[C:30]([O:35][CH3:36])[CH:31]=[C:32]([O:33][CH3:34])[C:27]=1[CH:20]([S:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:17][CH:18]=1)[CH2:21][N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1
Reactant: COC(=O)c1ccc(S)cc1
Reactant: COc1cc(OC)c(C(O)Cn2ccnc2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(SC(Cn2ccnc2)c2c(OC)cc(OC)cc2OC)cc1
Reaction time: 2 h
Yield: 94.3 %

Procedure:
13.5 ml of trifluoroacetic acid were added, whilst ice-cooling, to a mixture of 940 mg of methyl 4-mercaptobenzoate and 1.04 g of 1-[2-hydroxy-2-(2,4,6-trimethoxyphenyl)ethyl]imidazole, and the resulting mixture was stirred at a temperature between 0° and 5° C. for 2 hours. The reaction mixture was then treated and purified in a similar manner to that described in Example 13 to give 1.51 g of the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10]2C(=C(CBr)[C:7]([Cl:17])=[CH:8][CH:9]=2)[N:4]=1.S(=O)(=O)(O)O.[N+]([O-])(O)=O.[C:31]([OH:35])(=[O:34])[CH2:32][CH3:33]>O>[F:1][C:2]([F:20])([F:21])[C:3]1[C:12]([C:13]([F:15])([F:16])[F:14])=[CH:11][C:10]2[C:33](=[C:32]([C:31]([OH:35])=[O:34])[C:7]([Cl:17])=[CH:8][CH:9]=2)[N:4]=1
Reactant: CCC(=O)O
Reactant: FC(F)(F)c1cc2ccc(Cl)c(CBr)c2nc1C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: O=[N+]([O-])O
Solvent: O
Product: O=C(O)c1c(Cl)ccc2cc(C(F)(F)F)c(C(F)(F)F)nc12
Reaction time: 2 h
Yield: 80.9 %

Procedure:
2.4 g of 2,3-bis-(trifluoromethyl)-8-bromomethyl-7-chloroquinoline are suspended in 6.8 g of propionic acid and 6.8 g of 70% strength sulfuric acid, and 5.5 g of 65% strength nitric acid are added dropwise at 120° C. After 2 hours at 120° C., the mixture is diluted with water and the precipitate is filtered off under suction, washed and dried; 1.7 g (84%) of 2,3-bis-(trifluoromethyl)-7-chloroquinoline-8-carboxylic acid of melting point 108°-111° C. are isolated.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]([N:13]1[C@H:18]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:17](=[O:23])[NH:16][C@H:15]([CH:24]2[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25]2)[C:14]1=[O:33])[C:10]([OH:12])=[O:11].C(=O)([O-])[O-].[K+].[K+].[C:40]([O:43][CH:44](Br)[CH3:45])(=[O:42])[CH3:41]>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]([N:13]1[C@H:18]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:17](=[O:23])[NH:16][C@H:15]([CH:24]2[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25]2)[C:14]1=[O:33])[C:10]([O:12][CH:44]([O:43][C:40](=[O:42])[CH3:41])[CH3:45])=[O:11]
Reactant: CC(=O)OC(C)Br
Reactant: CC(C)C[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1[C@@H](C(=O)O)c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OC(C)OC(=O)[C@@H](c1ccc(F)cc1F)N1C(=O)[C@@H](C2Cc3ccccc3C2)NC(=O)[C@H]1CC(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(2R)-(2,4-difluorophenyl)[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]ethanoic acid (example 22) (0.130 g) was stirred in anhydrous DMF (1 mL) and anhydrous potassium carbonate (0.020 g, 0.5 eq.) was added. The mixture was stirred at room temperature for 1 hour then cooled to −10° C. (ice-salt bath). The heterogeneous mixture was treated with 1-bromoethyl acetate (0.120 mL, excess) and stirred for 3.5 hours keeping the bath temperature between −10 and −5° C. It was then partitioned between DCM and 1M HCl aq. (20 mL each). The organic phase was separated (hydrophobic frit) and evaporated under reduced pressure to give a purple gum; this was purified by SPE cartridge (5 g, silica eluted with (i) cyclohexane×2, (ii) DCM×2, (iii) diethyl ether×2, (iv) ethyl acetate×2, (v) methanol×2 to give 1-(acetyloxy)ethyl (2R)-(2,4-difluorophenyl)[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]ethanoate (0.081 g) as a yellow foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15]Cl)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18].[CH2:21]([C:23]1[C:24](=[O:30])[NH:25][C:26](=[S:29])[NH:27][CH:28]=1)[CH3:22].CCN(C(C)C)C(C)C>ClCCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][S:29][C:26]3[NH:27][CH:28]=[C:23]([CH2:21][CH3:22])[C:24](=[O:30])[N:25]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18]
Reactant: CCc1c[nH]c(=S)[nH]c1=O
Reactant: FC(F)(F)c1cc(Oc2ccc(CCl)cc2)ccc1Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1c[nH]c(SCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)nc1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 46 %

Procedure:
A mixture of 1-chloro-4-{[4-(chloromethyl)phenyl]oxy}-2-(trifluoromethyl)benzene (65 mg, 0.202 mmol), 5-ethyl-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone (47.4 mg, 0.304 mmol) and DIPEA (0.163 mL, 0.933 mmol) in DCE (3.0 mL) was sealed in a vessel and stirred at room temperature for 5 min, then was heated with a microwave condition at 80° C. for 30 min. After cooling, the reaction was quenched with water, extracted with EA, the combined organic layers were dried with sodium sulfate, concentrated, and purified via MDAP to afford the title compound (41 mg, 45.9% yield). LCMS: rt=3.94 min, [M+H+]=441
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:12])[CH:6]=[CH:7][C:8]=1[Cl:9].C(OC([N:26]1[CH2:31][CH2:30][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:28][C@@H:27]1[C:35](O)=[O:36])=O)(C)(C)C.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(NC(C)C)(C)C>C1COCC1>[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:35]([C@H:27]3[CH2:28][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:30][CH2:31][NH:26]3)=[O:36])[CH2:15][CH2:14]2)=[O:12])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCNCC1
Reactant: CC(C)N1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCN[C@@H](C(=O)N2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Reaction time: 4 h
Yield: 30.2 %

Procedure:
N-(3,4-Dichlorophenyl)piperazine-1-carboxamide hydrochloride (251 mg) and (2R)-1-(tert-Butoxycarbonyl)-4-isopropylpiperazine-2-carboxylic acid (200 mg) were dissolved in dry THF (10 mL) followed by addition of N,N-di-isopropylethylamine (0.26 ml) and HATU (335 mg) and the reaction was stirred for 4 h. A further 0.26 ml of N,N-di-iso-propylamine was added and the reaction was stirred for 18 h at rt. The solvent was evaporated under reduced pressure then redissolved in dichloromethane (50 ml) followed by washing with sat. aqueous NaHCO3 (20 ml). The organic layer was separated on a phase separation cartridge and evaporated. Purification by chromatography (3-10% methanol:dichloromethane) afforded the crude product (180 mg) as a foam which was used without further purification. The foam was then dissolved in TFA/DCM (1:1, 10 ml) and stirred for 30 mins. The solvent was removed under reduced pressure then taken up in 1M. aqueous sodium hydroxide (30 ml) and extracted with dichloromethane (2×30 ml). The organic layer was separated on a phase separation cartridge and evaporated. Purification by chromatography (5-25% MeOH:DCM) afforded the title compound (95 mg) as a white foam.